A green tandem cyclization approach to substituted 2-aminothiazoles via molecular sieve/I₂ catalysis: DFT, molecular dockings, and pharmacokinetic profiles

Abstract

In an effort to promote eco-friendly organic synthesis, a facile, sustainable, and highly efficient procedure for the synthesis of 2-amino-1,3-thiazole derivatives was developed. The protocol of this process incorporates the principles of green chemistry. Moreover, the NMR, FT-IR, and UV simulations of the compounds were conducted at the B3LYP/6-311++G** level for comparison with the observed counterparts. FMO analyses revealed that the PhTA compound exhibited the highest stability via back-donation; among the compounds, NapTA exhibited the lowest stability via back-donation. Furthermore, the –NH₂ group did not influence electrophilic attacks because the LUMO for all compounds did not separate from this group. Also, the lipophilicity, solubility, pharmacokinetics, and drug-likeness profiles of the compounds were evaluated. The BOILED-Egg model implied that the compounds PhTA, BFTA, and NapTA permeate through the BBB (blood–brain-barrier) passively, while the FTA and ThTA compounds have no potency in terms of BBB penetration. Also, all compounds met the requested physicochemical criteria according to the Lipinski, Veber, and Egan rules. Additionally, the molecules were analyzed using the molecular docking method to gain insights into their possible anticancer activity. Vascular endothelial growth factor receptor-2, human estrogen receptor, human cytochrome P450, and human extracellular signal-regulated kinase 2 were selected. All the obtained results are expected to provide important insights into the structure–reactivity relationship in early-stage drug design research.

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1. Introduction

2-Aminothiazole is a heterocyclic aromatic amine characterized by a thiazole core, a five-membered ring system containing sulfur and nitrogen at the 1,3-positions, substituted with various functional groups.¹ The thiazole ring is a main structural motif and is applied extensively in different natural compounds, such as pharmaceutical drugs, biocides, and fungicides.² Moreover, thiazole derivatives are well known for their diverse biological activities and have been documented to exhibit both antimycobacterial and antiplasmodial effects. Molecules incorporating the 2-amino-4-(2-pyridyl)thiazole scaffold are of particular significance, especially when the amino group is substituted with aryl or aryl-alkyl functionalities.^3,4 Consequently, considerable efforts have been devoted to developing methods for the synthesis of 2-aminothiazoles.^5,6 Although numerous studies on the synthesis of 2-aminothiazoles have been reported in the literature, to the best of our knowledge, no research has focused on developing an environmentally friendly and efficient one-pot procedure for their synthesis using a green catalyst. In this work, we describe a concise, rapid, and efficient method for preparing aminothiazole derivatives through a one-pot reaction of various ketones with thiourea in the presence of ethanol and molecular sieves under reflux conditions (Scheme 1).⁷

Scheme 1 Synthetic pathway and proposed mechanism for 2-amino-1,3-thiazole derivatives.

Molecular docking, which predicts the details of the interactions between drug-candidate small molecules and larger target molecules, is a crucial computational technique in drug discovery and biochemistry. This technique not only suggests the binding types, sites, and orientation of the interactions but also assists in revealing the action mechanisms of drug candidates.⁸ Additionally, this method reduces the time and labor costs of drug discovery studies. On the other hand, correct target selection can provide reliable binding predictions and selectivity.⁹ In this study, vascular endothelial growth factor receptor-2 (VEGFR-2),¹⁰ human estrogen receptor,¹¹ human cytochrome P450,¹² and human extracellular signal-regulated kinase 2 (ERK2)¹³ were selected as target molecules to analyze the possible anticancer activities of the molecules.

Recently, the optical absorption spectra of functionalized cyclopropylthiazole derivatives were investigated by using PBE0/6-311++G(d,p) level computations to elucidate the electronic characteristics.¹⁴ Moreover, halogen-substituted phenylthiazoleamine derivatives were explored for their α-glucosidase inhibition potency, and B3LYP/6-311G(d,p) simulations were performed to elucidate the possible reactivity tendencies of the compounds.¹⁵ In research developing the synthetic methodology, the photochemical behavior of 2-aminothiazole derivatives was evaluated with DFT simulations to gain a deep understanding of the key electronic features underlying the phototransformations.¹⁶ Recently, the UV-induced photodegradation of 2-aminothiazole-4-carboxylic acid derivatives was investigated using B3LYP-D3/6-311++G(3df,3pd) to determine photolysis pathways.¹⁷ Additionally, the newly synthesized and characterized aminothiazole-based dyes were investigated using B3LYP/6-311G** and Cam-B3LYP 6-311 G++(d,p) levels to explore the electronic and UV-Vis characteristics of the data set.¹⁸ Moreover, a series of N-(thiazol-2-yl)piperidine-2,6-dione derivatives were prepared and characterized by X-ray crystallography; then, SHG “second-harmonic-generation” features were explored: UV spectroscopic computations were performed to verify the SHG phenomenon.¹⁹ Two new 2-naphthol-thiazole-azo compounds were synthesized and investigated for their anticancer and antioxidant potencies; DFT/B3LYP/6-31+G (d) computations were performed to elucidate the reactivity behaviors.²⁰

Herein, the combined experimental and theoretical studies of the compounds (Scheme 2) were performed to synthesize 2-aminothiazoles via a green pathway; then, in silico simulations were performed to predict and evaluate the electronic, spectroscopic, and physicochemical behaviors as well as the molecular dockings.

Scheme 2 Chemical structures of 2-aminothiazoles.

2. Experimental and computational methods

2.1. Materials and measurement

The ¹H and ¹³C NMR spectra were obtained using a Bruker instrument DPX-400 MHz High Performance Digital FT-NMR Spectrometer in CDCl₃ and DMSO-d₆ as solvents, with tetramethyl silane (TMS) as the internal standard at 25 °C. Chemical shifts (δ) are reported in parts per million (ppm), and coupling constants (J) are reported in hertz (Hz). FT-IR spectra were recorded on a Matson-1000 spectrophotometer using KBr pellets within the 400–4000 cm⁻¹ wavenumber range. Melting points were determined using a Gallenkamp apparatus and capillary tubes. The UV spectrum was measured using Shimadzu UV-vis spectrophotometer 2600. Reaction progress was monitored by thin-layer chromatography (TLC) on silica gel 60 F₂₅₄ plates. All reagents and solvents were obtained from commercial sources, and reactions were carried out under a nitrogen atmosphere after proper solvent purification.

2.2. General procedure for the preparation of the synthesis of reagents and products

2.2.1. General procedure for the synthesis of 2-aminothiazole derivatives. A mixture of acetophenone 1 (600 mg, 5 mmol), iodine (400 mg, 5 mmol), and molecular sieves (3 Å, 10.0 g) in anhydrous 50 mL of EtOH was refluxed for 1 h, and the progress of the reaction was monitored by TLC. After completion, thiourea 2 (380 mg, 5 mmol) was added, and the mixture was further refluxed for 1 h in a nitrogen atmosphere. After completion of the reaction, the mixture was allowed to cool to room temperature, and the solvent was removed under reduced pressure. The resulting residue was extracted with EtOAc, followed by extraction and washing with 10% Na₂SO₃ solution. The residue was diluted with 30 mL of 10% NaHCO₃ solution and extracted with ethyl acetate. Purification of the residue by silica gel chromatography using chloroform as the eluent afforded the expected products PhTA (94%), BFTA (86%), FTA (78%), ThTA (75%), and NapTA (67%) in yield.

2.2.2. 4-Phenyl-2-aminothiazole (PhTA). White solid, 827 mg yield 94%, mp: 151–152 °C, R_f 0.33 (EtOAc). UV (MeOH), λ_max 280, 332 nm. IR spectrum (KBr, ν): 3430, 3241, 3121, 1591, 1523, 1477, 1442, 1334, 1301, 1193, 1068, 1032, and 1024 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 5.48 and 5.59 (2s, 2H), 6.85 (s, 1H), 7.28 (dd, 1H, J = 7.6 Hz), 7.35 (t, 2H, J = 7.4 Hz), and 7.75 (d, 2H, J = 7.8 Hz); ¹³C NMR (100 MHz, CDCl₃): δ = 101.6, 124.4, 126.9, 127.5, 128.3, 129.3, 135.5, 152.1, and 168.4.

Found, %: C, 61.27; H, 4.64; and N, 15.82. C₉H₈N₂S. Calcd, %: C, 61.34; H, 4.58; and N, 15.90.

2.2.3. 4-(1,3-Dihydroisobenzofuran-5-yl)-2-aminothiazole (BFTA). White solid, 937 mg, yield 86%, mp: 114–116 °C, R_f 0.28 (EtOAc). UV (MeOH), λ_max 322, 438 nm. IR spectrum (KBr, ν): 3435, 3289, 3119, 1923, 1634, 1532, 1493, 1480, 1443, 1323, 1296, 1243, 1192, 1123, and 1035 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆): δ = 3.43 (s, 4H), 6.11 (s, 2H), 6.85-6.94 (m, 1H), 7.02 (s, 2H), and 7.33 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ = 101.1, 102.1, 104.9, 107.3, 118.4, 128.5, 145.4, 146.2, 148.1, 148.5, and 167.1.

Found, %: C, 60.44; H, 4.57; and N, 12.94. C₁₁H₁₀N₂OS. Calcd, %: C, 60.53; H, 4.62; and N, 12.83.

2.2.4. 4-(Furan-2-yl)-2-aminothiazole (FTA). White solid, 714 mg, yield 86%, mp: 125–126 °C, R_f 0.51 (EtOAc). UV (MeOH), λ_max 254, 334 nm. IR spectrum (KBr, ν): 3431, 3268, 3108, 2962, 1631, 1524, 1452, 1381, 1324, 1211, 1148, 1041, 1002, and 801 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆): δ = 6.51 (d, 2H, J = 4.7 Hz), 6.73 (s, 1H), 7.10 (s, 2H), and 7.62 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ = 101.5, 105.0, 112.6, 140.8, 141.2, 151.6, and 167.6.

Found, %: C, 50.64; H, 3.57; and N, 16.93. C₇H₆N₂OS. Calcd, %: C, 50.59; H, 3.64; and N, 16.86.

2.2.5. 4-(Thiophen-2-yl)-2-aminothiazole (ThTA). White solid, 698 mg, yield 75%, mp: 134–135 °C, R_f 0.41 (EtOAc). UV (Me), λ_max 309, 341 nm. IR spectrum (KBr, ν): 3342, 3260, 2921, 1627, 1554, 1518, 1361, 1321, 1283, 1077, and 1048 cm⁻¹. ¹H NMR (400 MHz, CDCl₃): δ = 5.53 (s, 2H), 6.58 (s, 1H), 7.01 (t, 1H, J = 4.7 Hz), 7.20 (d, 1H, J = 4.5 Hz), and 7.30 (d, 1H, J = 3.4 Hz); ¹³C NMR (100 MHz, CDCl₃): δ = 102.2, 122.5, 123.4, 127.5, 137.5, 144.3, and 166.6.

Found, %: C, 46.19; H, 3.28; N, and 15.31. C₇H₆N₂S₂. Calcd, %: C, 46.13; H, 3.32; and N, 15.37.

2.2.6. 4-(Naphthalen-2-yl)-2-aminothiazole (NapTA). White solid, 758 mg, yield 67%, mp: 157–158 °C, R_f 0.33 (EtOAc). UV (MeOH), λ_max 314, 348 nm. IR spectrum (KBr, ν): 3421, 3244, 3121, 2922, 1621, 1589, 1523, 1493, 1358, 1327, 1180, and 1031 cm⁻¹. ¹H NMR (400 MHz, DMSO-d₆): δ = 7.10 (s, 2H), 7.48–7.52 (m, 2H), 7.87–7.97 (m, 5H), and 8.35 (s, 1H); ¹³C NMR (100 MHz, DMSO-d₆): δ = 101.5, 123.1, 124.8, 125.8, 126.4, 126.8, 127.5, 127.9, 128.1, 131.3, 132.1, 148.8, and 167.2.

Found, %: C, 60.06; H, 4.39; and N, 12.27. C₁₃H₁₀N₂S. Calcd, %: C, 69.00; H, 4.45; and N, 12.38.

2.3. Molecular docking methods

VEGFR-2 (pdb: 1ywn),²¹ human estrogen receptor (pdb: 3ert),²² human cytochrome P450 (pdb: 3ruk),²³ and human ERK2 (pdb: 4qta)²⁴ crystal structures were downloaded from the RCSB protein data bank (https://www.rcsb.org/). AutoDockTools 4.2 was used for all molecular docking performances.^25,26 The biomacromolecules were first recorded in pdbqt format, which was used as rigid molecules during the performances. The polar hydrogens and Kollman charges were evaluated, while the water molecules were removed from the target molecules before the processes in which Lamarckian genetic algorithms, such as 150, were considered.^27,28 The 2-aminothiazole-type molecules were also recorded as pdbqt using Gasteiger charges.²⁹ All the illustrations of the results were drawn and prepared using Discovery Studio 4.1.0.

2.4. DFT studies

B3LYP^30,31/6-311++G** level³² simulations of the compounds were performed using G16W³³ by default settings.^34,35 The visualizations of the quantum chemical computations were made using GaussView 6.0.16 (ref. 36) software. The calculated vibrational modes of the compounds were scaled down by 0.96 (high) and 0.988 (low) to make them comparable to the experimental modes.³⁷ The NMR shifts were calculated at the same level of the theory using the GIAO “Gauge-Independent Atomic Orbital”^38,39 method in the related simulation media depending on the observed media. Furthermore, the TD-DFT/B3LYP/6-311++G** level^40,41 simulations were performed in the methanol phase, which was the solvent used in recording the experimental spectra. The PCM (polarizable continuum model)^42,43 was used to simulate the related solvent media in this work. The basis of statistical mechanics principles was used to predict and evaluate the thermochemical and physicochemical data of the synthesized compounds.^44–46

The global reactivity parameters obtained from I (ionization energy) and A (electron affinity)⁴⁷ resulted in the following equations:

I = −E_HOMO,

A = −E_LUMO,

ω⁺ ≈ (I + 3A)²/(16(I − A)),

ω⁻ ≈ (3I + A)²/(16(I − A)),

where χ denotes the electronic chemical potential, η denotes the global hardness, ω denotes the electrophilicity, ΔN_max denotes the maximum charge transfer capability index,^48–53 ω denotes the electron-donating power, ω⁺ denotes the electron-accepting power,⁵⁴ and ΔE_back-donat. denotes the back-donation energy.⁵⁵

2.5. Physicochemistry, ADMET, and druglikeness

The LOGP “lipophilicity”, LOGS “water-solubility”, pharmacokinetics profiles, and drug-likeness features of synthesized compounds PhTA, BFTA, FTA, ThTA, and NapTA were calculated using SwissADME⁵⁶ tools. Herein, the LOGP scores of the compounds were evaluated in light of 5 approaches, such as ILOGP,⁵⁷ XLOGP3,⁵⁸ WLOGP,⁵⁹ MLOGP,⁶⁰ and SILICO-IT.⁶¹ As is well known, the LOGP value is described as follows:
where C_o denotes the concentrations of the neutral molecule in octanol and C_w denotes the concentrations of the neutral molecule in water.

Moreover, the log S values are given by the following formulae:

log S_w = 0.16–0.63 c log P − 0.0062 MWT + 0.066 RB − 0.74 AP (ESOL),⁶²

log S_w = −1.0239 log P − 0.0148 TPSA − 0.0058 (m.p. (C) − 25) + 0.3295 aroOHdel + 0.5337 (ALI).⁶³

The terms are described as MWT “molecular weight”, RB “rotatable bonds”, AP “aromatic proportion”, TPSA “topological surface area”, aroOHdel “aromatic –OH group number”, and MP “melting point”.

The drug-likeness properties of the compounds were determined using the Lipinski,⁶⁰ Ghose,⁶⁴ Veber,⁶⁵ Egan,⁶⁶ and Muegge⁶⁷ approaches. The Abbott⁶⁸ index was used to appraise the bioavailability of the data set, whose molecular structure and physicochemical features are depicted in Table 1.

Table 1 Physicochemical properties

	PhTA	BFTA	FTA	ThTA	NapTA
a TPSA, “topological polar surface area”; HBA, “hydrogen bond acceptor”; HBD, “hydrogen bond donor”; RB, “rotatable bonds”; AHA, “aromatic heavy atoms”; and Ref, “refractivity”.
Formula	C9H8N2S	C11H10N2OS	C7H6N2OS	C7H6N2S2	C13H10N2S
MW (g mol^−1)	176.24	218.27	166.20	182.27	226.30
Num. HA	12	15	11	11	16
Num. AHA	11	11	10	10	15
Fraction Csp^3	0.00	0.18	0.00	0.00	0.00
Num. RB	1	1	1	1	1
Num. HBA	1	2	2	1	1
Num. HBD	1	1	1	1	1
Molar ref.	51.95	60.86	44.22	49.83	69.46
TPSA (Å^2)^a	67.15	76.38	80.29	95.39	67.15

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3. Results and discussion

3.1. Synthesis and spectroscopic characterization

The reaction of acetophenone 1 with thiourea 2 was carried out under the conditions described in this study. As part of our ongoing investigation into the use of molecular sieves in heterocyclic synthesis, the same methodology was applied to other substrates under similar conditions. Acetophenone 1 was selected as the model compound for the optimization of the reaction parameters. To determine the most suitable solvent, a series of reactions was performed using different solvents. The results are summarized in Table 2. Among the solvents tested, ethanol proved to be the most effective. In the presence of molecular iodine, molecular sieves, and thiourea 2, acetophenone 1 was efficiently converted to the desired product in 94% yield after refluxing for 2 h (Table 2, entry 8). Reactions conducted under reflux consistently afforded higher yields than those performed at room temperature. Reaction progress was monitored using thin-layer chromatography (TLC). Upon completion, the mixture was treated with 30 mL of 10% NaHCO₃ solution and extracted with ethyl acetate. The combined organic layers were dried over MgSO₄, and the solvent was removed under reduced pressure to afford the crude product (see the Experimental section). Other solvents, including THF, DMF, MeCN, MeOH, dioxane, toluene, DMSO, and CH₂Cl₂, were also evaluated but were significantly less effective than ethanol. Consequently, ethanol was identified as the optimal solvent for the synthesis of the corresponding products (PhTA, BFTA, FTA, ThTA, and NapTA). Subsequently, different molar ratios of the reactants were examined. A 1 : 1 molar ratio provided the highest yield, and increasing the amount of thiourea 2 to three equivalents did not improve the outcome. Therefore, the optimal conditions for PhTA formation were established as refluxing equimolar amounts of acetophenone 1 and thiourea 2 in ethanol (Table 2, entry 8). The structure of the synthesized compound was confirmed by ¹H and ¹³C NMR as well as IR spectroscopy. An examination of the proton NMR spectra showed that the NH₂ signals at 5.48 and 5.59 ppm in the ¹H NMR spectrum were associated with the PhTA structure. For BFTA, the resonance observed at 6.11 ppm was assigned to the NH₂ group, while the signal at 3.43 ppm was attributed to the CH₂ protons. The synthesized compounds were also confirmed by analyzing their FT-IR and ¹³C NMR spectra. Additionally, a series of substituted 2-aminothiazoles (PhTA, BFTA, FTA, ThTA, and NapTA) was synthesized in good yields, and a plausible reaction mechanism was proposed (Scheme 1). In our previous studies, molecular sieves were employed; in the present study, we further supported green chemistry principles using ethanol as a solvent in combination with molecular sieves. Table 3 provides a comparative analysis of the current methodology against previously reported literature, highlighting differences in catalysts, temperature ranges, and reaction yields.^69–72 This strategy offers a new approach to the synthesis of various aromatic compounds.

Table 2 Optimization of reaction conditions

Entry	1 (equiv.)	2 (equiv.)	Solvents	Conditions	Yield (%)
1	1.0	1.0	THF	25 °C	27
2	1.0	1.0	THF	Reflux	41
3	1.0	1.0	DMF	25 °C	44
4	1.0	1.0	DMF	Reflux	51
5	1.0	1.0	MeCN	25 °C	47
6	1.0	1.0	MeCN	Reflux	63
7	1.0	1.0	EtOH	25 °C	51
8	1.0	1.0	EtOH	Reflux	94
9	1.0	3.0	EtOH	Reflux	93
10	1.0	1.0	MeOH	25 °C	51
11	1.0	1.0	MeOH	Reflux	87
12	1.0	1.0	Dioxane	25 °C	55
13	1.0	1.0	Dioxane	Reflux	64
14	1.0	1.0	Toluene	25 °C	44
15	1.0	1.0	Toluene	Reflux	67
16	1.0	1.0	DMSO	25 °C	38
17	1.0	1.0	DMSO	Reflux	61
18	1.0	1.0	CH2Cl2	25 °C	35
19	1.0	1.0	CH2Cl2	Reflux	48

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Table 3 Comparison of the synthesis of substituted 2-aminothiazole (PhTA) derivatives

Entry	Catalyst/solvent	Temperature (°C)	Time (h)	Yield^a (%)	References
a Isolated yield.
1	Ca/4-MePy-IL@ZY-Fe3O4/EtOH	80	1.5	90	69
2	Nanochitosan (EtOH)	Reflux (80)	2.5	95	70
3	FeCl3·6H2O (20 mol%)/PEG-400/CH3CN	110	24	58	71
4	I2/DMSO	80	12	53	72
5	Molecular sieve/I2/EtOH	Reflux	2	94	This study

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Given the broad applications of thiazoles in medicinal chemistry, this method represents an efficient and environmentally friendly synthetic route. Moreover, the protocol proved applicable to the preparation of structurally diverse 2-aminothiazole derivatives from commercially available ketones. Although NapTA was obtained in a relatively lower yield due to the formation of unidentified by-products, this outcome further highlights the synthetic utility of the method, as other aromatic and heterocyclic derivatives were produced in significantly higher yields than the naphthalene analogue.

3.1.1. FT-IR spectra. FT-IR spectroscopy is one of the essential methods for analyzing functional group(s) in relevant molecular systems and plays an important role in synthetic chemistry. In this work, the observed and calculated IR spectra of the synthesized compounds are presented in Fig. S1–S5; the calculated vibrations are summarized in Table S1 (SI data).

Related to the primary amine group, the apparent peaks at 3430 and 3421 cm⁻¹ of the PhTA compound were related to the asymmetric and symmetric bond elongation modes of the NH₂ group assigned at 3529 and 3425 cm⁻¹, respectively. Furthermore, the νNH_2(as.) modes for the BFTA, FTA, ThTA, and NapTA compounds were observed at 3435, 3431, 3342, and 3421 cm⁻¹, respectively, whereas they were assigned at 3531, 3528, 3531, and 3530 cm⁻¹. From Table S1, the apparent peak of the PhTA compound at 3121 cm⁻¹ was simulated in the range of 3129-3033 cm⁻¹ and related to the C–H bond elongation. The recorded peaks of the PhTA, BFTA, FTA, ThTA, and NapTA compounds at 1591, 1634, 1631, 1627, and 1621 cm-1 of the compounds were calculated at 1628, 1627, 1629, 1628, and 1628 cm⁻¹, respectively, and were related to the NH₂ bending mode. Moreover, the βNH₂ mode and νCC mode of the PhTA compound were calculated and recorded at 1622 and 1523 cm⁻¹, respectively. The νN=C stretching mode for the PhTA compound was assigned and observed at 1559 and 1477 cm⁻¹, respectively, while the νN=C for the NapTA compound was observed and calculated at 1493 and 1558 cm⁻¹. However, the single bond N–H stretching for the BFTA and FTA compounds was recorded at 1443 and 1324 cm⁻¹, respectively, and computed in the ranges of 1331–1286 and 1330–1293 cm⁻¹, respectively. The νC–O modes for the BFTA and FTA compounds were recorded at 1035 and 1041 cm⁻¹, respectively, and assigned at 1061 and 905 as well as at 1229 and 1094 cm⁻¹. Recently, the C–O single bond stretching for pyrrole derivatives was recorded in the range of 1258–1047 cm⁻¹ and predicted with the B3LYP/6-311G** level simulations in 1241–1003 cm⁻¹.⁷ Additionally, the νN=C stretching for the pyrazine derivatives was calculated by the B3LYP/6-311 G** level in the range of 1581–1110 cm⁻¹ (ref. 73) and recorded in 1544–1336 cm⁻¹ for the pyrrole derivatives.^7,74 The aromatic C–H bond stretching was recorded at 3099 and 3043 cm⁻¹, which were assigned by PED analysis in 3130 (99% PED) and 3087 cm⁻¹ (100% PED), respectively.⁷⁵ In previous studies, the νNH mode for dasycarpidone was observed at 3221 cm⁻¹ and predicted at 3507 cm⁻¹ (100% PED) using B3LYP/6-311 G(d,p) level computations.⁷⁶

3.1.2. ¹³C NMR and ¹H NMR spectra. In synthetic chemistry, NMR spectroscopy is also a key analytical tool that provides deep information about the chemical environment and dynamics of the related systems. The observed ¹H and ¹³C NMR spectra of the compounds are presented in Fig. S6–S10, S11–S15, respectively, in the SI data; the related numerical data of the chemical shifts are presented in Table S2.

For the PhTA compound, the sp²-hybridized Cs gave peaks of the ¹³C NMR spectrum in the range of 101.6–168.4 ppm, which were assigned in the range of 114.0–178.1 ppm. Moreover, the largest chemical shifts of the PhTA compound were determined at 168.4 and 152.1 ppm for the C12 and C13 atoms, respectively, bonded to the electronegative N atom, while they were calculated at 178.1 and 157.9 ppm. Similarly, the corresponding C shifts for the BFTA compound were calculated at 179.3 and 157.8 ppm, respectively, and observed at 167.1 and 148.5 ppm. However, the sp³-hybridized Cs showed peaks at 101.1 (C1) and 102.1 ppm (C3) and were assigned at 80.2 ppm. Furthermore, the C1 shift for the FTA, ThTA, and NapTA compounds appeared at 167.6, 166.6, and 167.2 ppm, respectively, whereas it was predicted at 179,8, 177.8, and 179,6 ppm, respectively, which were the highest C shifts for these compounds due to the presence of the electronegative atom. Additionally, the second-highest shift for the FTA compound was calculated and observed for the C10 atom bonded to the electronegative O atom at 159.6 and 151.6 ppm, respectively. For the FTA compound, the apparent peak at 140.8 ppm was associated with the shift of the C15 atom bonded to the O atom and was calculated at 149.4 ppm. Previously, aromatic C atom shifts, which were neighbors to the N atom, were observed at 128.5 and 138.3 ppm, and assigned at 136.88–145.23 ppm.⁷⁷ The Cs shifts of the phenyl carbons for the thiophene derivatives were recorded at 117.4–147.8 ppm and assigned at 130.6–157.7 ppm,^78,79 respectively.

Moreover, the largest proton shift for the PhTA compound appeared at 7.75; then, 7.37 ppm was associated with the H7 and H11 atoms assigned at 8.44 and 8.02 ppm, respectively. Similarly, the chemical shifts for the corresponding Hs of the BFTA compound were recorded at 7.33 ppm (H15, H16), and assigned at 8.25 ppm (H15) and 7.90 ppm (H16). Previously, the ¹H shifts in the aromatic ring of the tubifolidine compound were observed at 6.51–7.02 ppm, and simulated at 6.74–7.28 ppm using B3LYP/6-311++G(df,pd) level.⁸⁰ The proton shifts of the Hs belonging to the amine group for the PhTA compound showed peaks at 5.48 and 5.59 ppm, which were assigned to 4.45 and 4.88 ppm, respectively. Moreover, the shifts for the H8 and H9 of the compounds FTA and NapTA were calculated at 4.68 and 4.96 ppm as well as at 4.70 and 5.03 ppm, respectively, which were observed at 6.53 ppm and 7.10 ppm.

3.1.3. UV-vis absorption spectra. UV-vis spectroscopy is an analytical technique used to evaluate how much a sample absorbs radiation in the UV-vis region of the spectrum. In our previous studies, we evaluated the DNA and BSA-binding properties of organic molecular systems^81,82 using this technique. Herein, the simulated UV spectra of the compounds were evaluated to provide a deep insight into the nature of the absorption of the radiation of the related compound. The recorded and simulated absorption wavelengths of the compounds are summarized in Table 4; the recorded and simulated electronic spectra of the compounds are depicted in Fig. S16–S20 and 1, respectively.

Table 4 Theoretical UV-vis absorption characteristics in methanol

	Exp. (λ (nm))	State	Transitions	MO%	ΔE (eV)	λ (nm)	f
PhTA	332	1	H → L	(89.9%)	2.7516	451	0.0000
	280	4	H → L	(96.4%)	4.1275	300	0.2185
BFTA	438	1	H → L	(88.0%)	2.7437	452	0.0000
	322	4	H → L	(94.1%)	4.0561	306	0.2156
FTA		1	H → L	(95.6%)	2.5658	483	0.0000
	334	3	H → L	(98.7%)	4.1377	300	0.3356
	254	5	H → L + 1	(79.8%)	4.4634	278	0.0029
			H → L + 2	(7.8%)
ThTA	341	1	H → L	(94.2%)	3.5671	348	0.0000
	309	3	H → L	(98.1%)	3.9232	316	0.3369
NapTA		1	H → L	(78.3%)	2.4270	511	0.0000
			H − 1 → L	(8.8%)
			H − 1 → L + 1	(5.0%)
	348	3	H → L	(94.6%)	3.6063	344	0.1410
	314	6	H → L + 1	(46.1%)	3.9991	310	0.0526
			H − 1 → L	(40.2%)

---

Fig. 1 Simulated UV-vis spectra.

Accordingly, the first s → s₀ excitation for all compounds was related to the H → L transition even though their oscillator strengths were almost zero. From Fig. 2, the first transitions for the compounds PhTA, FTA, and ThTA were associated with the electron movement from the HOMO expanded on the whole surface to LUMO separated on the surface except for the amine group. However, the H → L transition for BFTA was related to the charge movement from the almost thiazole-amine and partially benzo-part of the dihydroisobenzofuran unit to the whole molecular surface except for the –NH₂ group. Furthermore, the recorded peak at 280 nm for the PhTA compound was simulated at 300 nm with f = 0.2185 and related to the H → L (96.4%) transition. Similarly, the apparent peaks at 322 nm and 309 nm for the BFTA and ThTA compounds were associated with the H → L interaction determined at 306 and 316 nm, respectively, with oscillator strengths of 0.2156 and 0.3369. Additionally, the recorded shoulder band at 438 nm for the BFTA compound was determined at 452 nm with the MO contribution of 88.0%. However, two peaks recorded at 334 and 254 nm for the FTA compound were predicted at 300 (f = 3356) and 278 nm (f = 0.0029), respectively; the first peak was related to H → L (98.7%), while the second peak was associated with H → L + 1 (79.8%) and H → L + 2 (7.8%) transitions. Additionally, the recorded peak at 348 nm for the NapTA compound was due to the H → L (94.6%) interaction calculated at 344 nm (f = 0.1410), while the second peak apparent at 314 nm was contributed by the H → L + 1 (46.1%) and H − 1 → L (40.2%) transitions simulated at 310 nm (f = 0.0526). Herein, all electronic movements for all compounds are due to the n → π* and π → π* transitions (see Fig. 2).

Fig. 2 HOMO and LUMO plots for s → s₀ transitions of the compounds.

3.2. Molecule structure and physicochemical properties

The structural optimization of the relevant systems is the first step to reliably proceed to further analyses and evaluations. Herein, the optimized structures of the compounds and their calculated structural data are presented in Fig. 3 and Table 5, respectively. Additionally, the fully optimized parameters of the compounds are illustrated in Tables S3–S7 in the SI material of this study.

Fig. 3 Optimized structures.

Table 5 Selected optimized parameters in the gas

Bond length (Å)	Exp.^a	PhTA	BFTA	FTA	ThTA	NapTA
a The experimental values are taken from previous reports.b Ref. 83.c Ref. 84.
S–C (=N)	1.75^b	1.77	1.77	1.77	1.77	1.77
S–C (=C)	1.74^b	1.74	1.74	1.74	1.75	1.74
N=C (–S)	1.30^c	1.30	1.30	1.30	1.30	1.30
C–NH2	1.33^b	1.38	1.38	1.38	1.38	1.38
C–C (in TA ring)	1.37^b	1.37	1.37	1.37	1.37	1.37
O–C		—	1.43	1.36	—	—
Bond angle (°)
S–C=N	115.98^c	114.70	114.72	114.85	114.67	114.70
C–S–C (in TA)	89.39^c	88.11	88.11	88.19	88.27	88.16
S–C–NH2	119.43^b	121.07	121.12	121.06	121.17	121.14
S–C=C	109.14^c	110.66	110.62	110.14	110.30	110.56
C=C–N	114.90^b	114.79	114.85	115.58	115.19	114.92
C–N=C	112.25^b	111.75	111.71	111.22	111.57	111.66
N–C–NH2	123.15^b	124.12	124.09	123.96	124.06	124.08
C–O–C		—	110.45	107.38	—	—
C–S–C		—	—	—	91.57	—

---

From Table 5, the S–C bond length that neighbored the N atom in the thiazole ring was calculated to be 1.77 Å for all compounds. Additionally, another S–C bond length in the thiazole ring was determined as 1.74 Å for the PhTA, BFTA, FTA, and NapTA compounds and as 1.75 Å for the ThTA compound. Previously, Toplak and co-workers reported the S–C lengths for the 2-aminothiazole at 1.75 Å and 1.74 Å.⁸³ Furthermore, the N=C and C–C lengths in the thiazole ring were predicted at 1.38 Å and 1.37 Å, respectively, while they were previously recorded⁸³ at 1.33 Å and 1.37 Å. However, the atomic distance between the C and N atoms of the amine group was determined herein at 1.38 Å, while the C–NH₂ length for the 2-amino-thiazole was reported at 1.33 Å.⁸³ The O–C length for BFTA was calculated at 1.43 Å, while this length for FTA was determined at 1.36 Å due to the sp² hybridization of the Cs in the furan unit of the compound and thus electron delocalization in the ring. In addition, the C–S–C angles in the thiazole ring for the compounds PhTA, BFTA, FTA, ThTA, and NapTA were calculated at 88.11°, 88.11°, 88.19°, 88.27°, and 88.16°, respectively, while the S–C=C bond angles for the compounds were determined at 110.66°, 110.62°, 110.14°, 110.30°, and 110.56°, respectively. In previous studies, the C–S–C and S–C=C angles for the substituted benzo[d]thiazol compound were recorded at 89.39° and 109.14°,⁸⁴ respectively. The S–C=N angles for PhTA, BFTA, FTA, ThTA, and NapTA were estimated at 114.70°, 114.72°, 114.85°, 114.67°, and 114.70°, respectively, with deviations of 1.28°, 1.26°, 1.13°, 1.31°, and 1.28° from the reported value of 115.98°.⁸³ The S–C–N, C=C–N, C–N=C, and N–C–N angles of the PhTA were computed at 121.07°, 114.79°, 111.75°, and 124.12°, respectively, while these angles for NapTA were determined at 121.14°, 114.92°, 111.66°, and 124.08°, respectively. The calculated data agreed with the recorded data of the structurally related compounds.

Moreover, Table 6 displays the calculated thermochemical parameters, dipole moments, and polarizability values of the verified structures of the compounds. In the gas phase, the ΔE values of the compounds PhTA, BFTA, FTA, ThTA, and NapTA were determined at −855.466389, −1008.093775, −853.273957, −1176.263149, and −1009.097559 au, respectively. Additionally, the ΔG values of the FTA and ThTA compounds were calculated as −853.309760 and −1176.300081 au, respectively, in gas. From Table 6, the thermal energies of the compounds decreased as the solvent dielectric constant increased, from the gas to DMSO media, except for NapTA. Moreover, the E_therm. (in kcal mol⁻¹) value order of PhTA was calculated as gas (101.823) > chloroform (101.726) > methanol (101.699) > DMSO (101.698), while the E_therm. (in kcal mol⁻¹) for NapTA was calculated in the order of gas (132.620) > chloroform (132.476) > DMSO (132.463) > methanol (132.462). However, the heat capacity of the compounds increased as the solvent dielectric constant increased, except for the NapTA compound. The C_v (in cal mol⁻¹ K⁻¹) orders of FTA and NapTA compounds were determined as gas (35.740) > chloroform (35.848) > methanol (35.892) > DMSO (35.895) and gas (51.403) > DMSO (51.506) > methanol (51.510) > chloroform (51.529), respectively. Furthermore, the S (in cal mol⁻¹ K⁻¹) value of the PhTA compound decreased as the solvent dielectric constant increased, and the order was determined as gas (100.716) > chloroform (100.589) > methanol (100.358) > DMSO (100.350). However, the S (in cal mol⁻¹ K⁻¹) value changed in the following order: gas (113.692) > DMSO (112.962) > methanol (112.945) > chloroform (112.905), which implied that the BFTA behaved more spontaneously in the gas phase and vice versa for the chloroform phase. Unlike BFTA, the NapTA compound behaved more randomly in chloroform media according to the calculated order of chloroform > M > DMSO > gas, and vice versa for the gas phase. Herein, it is important to recall that the greatest contribution to the entropy came from the vibrational freedom of the system; the highest entropy value was calculated for the NapTA compound in all simulation media due to having the highest number of atoms and thus the highest number of vibrational modes among the compounds. For instance, the entropy orders in the gas and DMSO phases were predicted as NapTA (112.969) > BFTA (113.692) > PhTA (100.716) > ThTA (100.438) > FTA (97.005) and NapTA (113.683) > BFTA (112.962) > ThTA (100.625) > PhTA (100.350) > FTA (97.110), respectively. From Table 6, both dipole moment and polarizability values increased with an increase in the dielectric constant of the solvent media. The µ (in D) of FTA and ThTA compounds were calculated as follows: gas (1.48) > chloroform (2.09) > methanol (2.41) > DMSO (2.43) and gas (1.84) > chloroform (2.42) > methanol (2.69) > DMSO (2.71), respectively. Additionally, the order of µ (in D) of the compounds was determined as FTA < ThTA < PhTA < NapTA < BFTA in gas and FTA < PhTA < NapTA < ThTA < BFTA in the other simulation media. However, the polarizability (in au) order of the compounds was determined as follows: FTA < ThTA < PhTA < BFTA < NapTA in all simulation media. Accordingly, the NapTA could be more polarizable than the other compounds and vice versa for FTA.

Table 6 Thermochemistry and physicochemical values

		PhTA	BFTA	FTA	ThTA	NapTA
Gas (ε = 0.0)	ΔE (au)	−855.466389	−1008.093775	−853.273957	−1176.263149	−1009.097559
	ΔH (au)	−855.455365	−1008.080143	−853.263670	−1176.252360	−1009.083918
	ΔG (au)	−855.503218	−1008.134162	−853.309760	−1176.300081	−1009.137593
	Etherm. (kcal mol^−1)	101.823	128.070	82.272	80.519	132.620
	Cv (cal mol^−1 K^−1)	39.606	49.317	35.740	37.654	51.403
	S (cal mol^−1 K^−1)	100.716	113.692	97.005	100.438	112.969
	µ (D)	1.85	3.36	1.48	1.84	1.92
	α (au)	144.35	172.08	123.95	139.60	203.27
Chloroform (ε = 4.71)	ΔE (au)	−855.473444	−1008.102644	−853.282474	−1176.270651	−1009.105486
	ΔH (au)	−855.462415	−1008.089063	−853.272179	−1176.259844	−1009.091781
	ΔG (au)	−855.510207	−1008.142708	−853.318157	−1176.307455	−1009.145953
	Etherm. (kcal mol^−1)	101.726	128.001	82.139	80.411	132.476
	Cv (cal mol^−1 K^−1)	39.663	49.361	35.848	37.746	51.529
	S (cal mol^−1 K^−1)	100.589	112.905	96.768	100.205	114.014
	µ (D)	2.36	4.03	2.09	2.42	2.40
	α (au)	181.51	214.21	154.19	176.71	258.10
	ΔEsol./(kJ mol^−1)	18.52	23.29	22.36	19.70	20.81
	ΔHsol./(kJ mol^−1)	18.51	23.42	22.34	19.65	20.64
	ΔGsol./(kJ mol^−1)	18.35	22.44	22.05	19.36	21.95
Methanol (ε = 32.61)	ΔE (au)	−855.476391	−1008.106316	−853.286083	−1176.273784	−1009.108753
	ΔH (au)	−855.465367	−1008.092735	−853.275772	−1176.262974	−1009.095066
	ΔG (au)	−855.513050	−1008.146398	−853.321872	−1176.310792	−1009.149102
	Etherm. (kcal mol^−1)	101.699	127.968	82.084	80.380	132.462
	Cv (cal mol^−1 K^−1)	39.670	49.386	35.892	37.756	51.510
	S (cal mol^−1 K^−1)	100.358	112.945	97.025	100.643	113.728
	µ (D)	2.59	4.28	2.41	2.69	2.60
	α (au)	198.33	233.46	167.64	193.73	282.90
	ΔEsol./(kJ mol^−1)	26.26	32.93	31.84	27.92	29.39
	ΔHsol./(kJ mol^−1)	26.26	33.06	31.77	27.87	29.27
	ΔGsol./(kJ mol^−1)	25.81	32.13	31.80	28.12	30.22
DMSO (ε = 46.83)	ΔE (au)	−855.476569	−1008.106537	−853.286305	−1176.273973	−1009.108947
	ΔH (au)	−855.465545	−1008.092956	−853.275991	−1176.263163	−1009.095263
	ΔG (au)	−855.513225	−1008.146627	−853.322131	−1176.310973	−1009.149278
	Etherm. (kcal mol^−1)	101.698	127.966	82.080	80.378	132.463
	Cv (cal mol^−1 K^−1)	39.670	49.387	35.895	37.756	51.506
	S (cal mol^−1 K^−1)	100.350	112.962	97.110	100.625	113.683
	µ (D)	2.60	4.30	2.43	2.71	2.61
	α (au)	199.38	234.68	168.48	194.80	284.47
	ΔEsol./(kJ mol^−1)	26.73	33.51	32.42	28.42	29.90
	ΔHsol./(kJ mol^−1)	26.73	33.64	32.35	28.36	29.79
	ΔGsol./(kJ mol^−1)	26.27	32.73	32.48	28.60	30.68

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Moreover, the solvent effect on the ΔE, ΔH, and ΔG (au) quantities of the compounds was calculated, as presented in Table 6. Accordingly, each solvent environment provided stability for each compound relative to that of the gas phase counterpart. The ΔG_sol./(kJ mol⁻¹) order of the compounds was determined as BFTA (22.44) > FTA (22.05) > NapTA (21.95) > ThTA (19.36) > PhTA (18.35) in chloroform, and the orders of the methanol and DMSO media were the same as this trend. Similarly, the calculated ΔH_sol. and ΔE_sol. values disclosed the order of BFTA > FTA > NapTA > ThTA > PhTA in all simulation media. These values implied that the BFTA and then FTA compounds exhibited the highest stability among the compounds and vice versa for the PhTA compound in all simulation media.

3.3. Lipophilicity and water solubility features

In drug-design research, the lipophilicity and solubility in water are two key physicochemical parameters, and their predictions using computational tools play a critical role in the evaluation of which structure can be proper or not for usage in the related research field.

From Table 7, the averaged log P_o/w values of the compounds changed in the following order: NapTA (3.09) > PhTA (2.13) > ThTA (2.10) > BFTA (2.03) > FTA (1.48); NapTA exhibited a more lipophilic feature among the compounds, and vice versa for FTA. However, the iLOGP approach revealed the log P_o/w order as NapTA (2.15) > BFTA (2.02) > FTA (1.74) > PhTA (1.69) > ThTA (1.66). Accordingly, all compounds could have the potential for oral bioavailability based on the iLOGP approach because the calculated lipophilicity values changed in the optimal range of −0.7 to +5.0.^56,57 Moreover, the XLOGP3 and WLOGP approaches showed the log P_o/w values of the compounds ordered in the orders of NapTA > PhTA > ThTA > BFTA > FTA and NapTA > ThTA > PhTA > BFTA > FTA, respectively. According to the MLOGP method, the lipophilicity order was determined as NapTA (2.27) > PhTA (1.32) > BFTA (1.04) > ThTA (0.72) > FTA (−0.16); all compounds could be orally active because their calculated indices were lower than 4.15.⁸⁵ Although the calculated lipophilicity indices showed slightly different rankings, they all indicated that NapTA exhibited the most lipophilic behavior. Moreover, the FTA compound is slightly lipophilic among the compounds according to all approaches, except for the iLOGP approach.

Table 7 Lipophilicity and water solubility

Lipophilicity	PhTA	BFTA	FTA	ThTA	NapTA
a The abbreviations are defined as follows: S, soluble and MS, moderately soluble.
log Po/w (iLOGP)	1.69	2.02	1.74	1.66	2.15
log Po/w (XLOGP3)	2.27	1.49	1.37	1.98	3.52
log Po/w (WLOGP)	2.40	2.13	1.99	2.46	3.55
log Po/w (MLOGP)	1.32	1.04	−0.16	0.72	2.27
log Po/w (SILICOS-IT)	2.98	3.46	2.45	3.70	3.95
Consensus log Po/w	2.13	2.03	1.48	2.10	3.09
Water solubility
log S (ESOL)	−2.98	−2.61	−2.34	−2.82	−4.09
Sol. (mg mL^−1) × 10^−2	18.7	53.7	75.9	27.3	1.85
Class	S	S	S	S	MS
log S (Ali)	−3.32	−2.70	−2.66	−3.61	−4.61
Sol. (mg mL^−1) × 10^−2	8.50	43.4	36.4	4.48	0.550
Class	S	S	S	S	MS
log S (SILICOS-IT)	−3.45	−3.75	−2.66	−2.72	−5.13
Sol. (mg mL^−1) × 10^−2	6.27	3.87	36.5	34.7	0.166
Class^a	S	S	S	S	MS

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In terms of pharmacokinetic features, the balance between lipophilicity and water solubility plays an essential role in the drug's effectiveness. The ESOL method revealed that the log S values of the compounds gave the order of FTA > BFTA > ThTA > PhTA > NapTA, while Ali's method gave the log S values that changed in the order of BFTA > FTA > PhTA > ThTA > NapTA. Additionally, the SILICO-IT approach presented the log S order of FTA > ThTA > PhTA > BFTA > NapTA. Herein, NapTA was determined to be slightly soluble in water according to all methods, as could be expected from the results of the lipophilicity index. In addition, the BFTA and FTA compounds, which include benzofuran and furan rings, respectively, are more soluble in water. As is well known, the solubility feature of a related system is classified by the quantity of the log S parameter as follows: insoluble < −10 < poorly −6 < moderately < −4 < soluble < −2 < very < 0 < highly.⁵⁶ Except for NapTA, all compounds were soluble in water because the calculated indexes of the compounds were located within the solubility limits.

3.4. Pharmacokinetics and druglikeness studies

Herein, the pharmacokinetics and bioavailability parameters of the compounds are illustrated in Tables 8 and 9, respectively. Additionally, the BOILED-Egg “Brain Or IntestinaL EstimateD permeation” model and radar graphs, which were obtained from the SwissADME⁵⁶ and ADMETLab3 (ref. 86) tools, are illustrated in Fig. 4, respectively.

Table 8 Pharmacokinetics of the studied compounds

	PhTA	BFTA	FTA	ThTA	NapTA
GI absorption	High	High	High	High	High
BBB permeant	Yes	Yes	No	No	Yes
P-gp substrate	No	Yes	No	No	Yes
CYP1A2 inhibitor	Yes	Yes	Yes	Yes	Yes
CYP2C19 inhibitor	No	Yes	No	No	Yes
CYP2C9 inhibitor	No	No	No	No	No
CYP2D6 inhibitor	No	No	No	No	No
CYP3A4 inhibitor	No	Yes	No	No	Yes
log Kp (skin permeation)/cm s^−1	−5.76	−6.57	−6.34	−6.01	−5.18

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Table 9 Drug-likeness and bioavailability values of the compounds

	PhTA	BFTA	FTA	ThTA	NapTA
Lipinski	Yes	Yes	Yes	Yes	Yes
Ghose	Yes	Yes	No; atoms < 20	No; atoms < 20	Yes
Veber	Yes	Yes	Yes	Yes	Yes
Egan	Yes	Yes	Yes	Yes	Yes
Muegge	No; MW < 200	Yes	No; MW < 200	No; MW < 200	Yes
Bioavail.	0.55	0.55	0.55	0.55	0.55

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Fig. 4 BOILED-Egg and radar graphs.

Accordingly, the GI absorption potency of all compounds was determined to be high, and all compounds were located in the white region of the BOILED-Egg (Fig. 4). In a previous study, it was reported by Daina and Zoete⁸⁷ that PSA lower than 142 Ų and log P between −2.3 and +6.8 provided a good HIA. Herein, the TPSA and consensus log P values of the compounds were predicted in the ranges of 67.15–95.39 Ų (see Table 1) and 1.48–3.09 (see Table 7), which confirmed the good GI absorption of the compounds.

The compounds PhTA, BFTA, and NapTA permeated through the BBB (blood–brain-barrier) passively, while FTA and ThTA compounds had no potency in terms of BBB-penetration. From Fig. 4, PhTA, BFTA, and NapTA appeared in the yolk region of the BOILED-Egg, but FTA and ThTA compounds were not placed in the yolk region. Additionally, the compounds BFTA and NapTA would be predicted to be effluated from the CNS by the glycoprotein since they appeared as blue dots in the BOILED-Egg model. On the other hand, the PhTA, FTA, and ThTA compounds appeared around the red dots, implying that these compounds were effluated from the CNS by the glycoprotein. Furthermore, all compounds could have inhibitory potency for the CYP1A2 gene. In terms of the cytochrome P450 enzyme, none of the compounds had potency for CYP2C9 and CYP2D6 inhibition. From Table 8, BFTA and NapTA compounds had inhibitory potency for CYP2C19 and CYP3A4 enzymes, while the other compounds did not. Herein, the log K_p (skin permeation) values of the compounds were predicted to be between −5.18 and −6.57 cm s⁻¹; the BFTA had slight skin permeability among the compounds, and the NapTA compound had more skin permeation. In previous studies, the log K_p (skin permeation) for famotidine and cortisone was reported at −7.63 cm s⁻¹ and −7.29 cm s⁻¹, respectively;⁸⁸ all compounds studied in this work could have more skin penetration capability than those of famotidine and cortisone. Except for NapTA, the physicochemical properties of all compounds met the bioavailability criteria due to the yellow line appearing between the lower (green) and upper (blue) limits. However, the log S of the NapTA was out of the lower limit; besides, the log P and log D quantities were out of the upper bioavailability limit.

Moreover, Table 9 shows the drug-likeness and bioavailability scores of the compounds. Accordingly, the Lipinski, Veber, and Egan rules indicate that all compounds could meet bioavailability criteria. However, the Ghose method revealed that the atom numbers of the FTA and ThTA compounds were lower than 20 and had one violation of oral bioavailability. Except for NapTA, none of the compounds met the bioavailability criteria because the molecular weights of all compounds were lower than 200 g mol⁻¹. The bioavailability scores of all compounds were predicted to be 0.55, as expected from the Lipinski rules.

3.5. FMO (Frontier molecular orbital) analysis and MEP (molecular electrostatic potential)

In computational research, the FMO analysis's results have provided molecular insight into the prediction and evaluation of the possible chemical reactivity trend and active site of the relevant systems. For a long time, this computational approach has been applied to various kinds of molecular systems.^89,90 Herein, the calculated parameters of the compounds are presented in Table 10 in four simulation media.

Table 10 Chemical reactivity parameters

	Gas					Chloroform
	PhTA	BFTA	FTA	ThTA	NapTA	PhTA	BFTA	FTA	ThTA	NapTA
H (−I) (eV)	−5.770	−5.794	−5.588	−5.605	−5.663	−5.821	−5.804	−5.637	−5.670	−5.721
L (−A) (eV)	−1.186	−1.267	−1.068	−1.298	−1.555	−1.276	−1.302	−1.170	−1.395	−1.666
ΔE (eV)	4.584	4.527	4.520	4.307	4.108	4.545	4.502	4.468	4.275	4.055
χ (eV)	−3.478	−3.531	−3.328	−3.451	−3.609	−3.548	−3.553	−3.403	−3.532	−3.693
η (eV)	2.292	2.264	2.260	2.154	2.054	2.272	2.251	2.234	2.138	2.027
ω (eV)	0.097	0.101	0.090	0.102	0.117	0.102	0.103	0.095	0.107	0.124
ω^+ (au)	0.044	0.047	0.039	0.048	0.060	0.047	0.048	0.043	0.052	0.065
ω^− (au)	0.171	0.176	0.162	0.175	0.192	0.177	0.179	0.168	0.182	0.201
ΔNmax (eV)	1.518	1.560	1.472	1.603	1.757	1.562	1.578	1.524	1.653	1.822
Δεback-donat. (eV)	−0.573	−0.566	−0.565	−0.538	−0.513	−0.568	−0.563	−0.558	−0.534	−0.507

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	Methanol					DMSO
	PhTA	BFTA	FTA	ThTA	NapTA	PhTA	BFTA	FTA	ThTA	NapTA
H (−I) (eV)	−5.859	−5.828	−5.677	−5.712	−5.764	−5.862	−5.830	−5.680	−5.714	−5.767
L (−A) (eV)	−1.326	−1.332	−1.221	−1.451	−1.723	−1.329	−1.334	−1.225	−1.455	−1.727
ΔE (eV)	4.533	4.496	4.456	4.260	4.041	4.533	4.496	4.455	4.259	4.040
χ (eV)	−3.592	−3.580	−3.449	−3.582	−3.743	−3.595	−3.582	−3.452	−3.585	−3.747
η (eV)	2.267	2.248	2.228	2.130	2.021	2.266	2.248	2.227	2.130	2.020
ω (eV)	0.105	0.105	0.098	0.111	0.127	0.105	0.105	0.098	0.111	0.128
ω^+ (au)	0.049	0.049	0.045	0.055	0.068	0.049	0.049	0.045	0.055	0.068
ω^− (au)	0.181	0.181	0.172	0.186	0.205	0.181	0.181	0.172	0.187	0.206
ΔNmax (eV)	1.585	1.593	1.548	1.681	1.853	1.586	1.594	1.550	1.683	1.855
Δεback-donat. (eV)	−0.567	−0.562	−0.557	−0.533	−0.505	−0.567	−0.562	−0.557	−0.532	−0.505

---

In the gas phase, the reactivity parameters exhibited the following orders:

HOMO (eV): FTA (−5.588) > ThTA (−5.605) > NapTA (−5.663) > PhTA (−5.770) > BFTA (−5.794), LUMO (eV): FTA (−1.068) > PhTA (−1.186) > BFTA (−1.267) > ThTA (−1.298) > NapTA (−1.555), ΔE (eV): PhTA (4.584) > BFTA (4.527) > FTA (4.520) > ThTA (4.307) > NapTA (4.108), χ (eV): FTA (−3.328) > ThTA (−3.451) > PhTA (−3.478) > BFTA (−3.531) > NapTA (−3.609), η (eV): PhTA (2.292) > BFTA (2.264) > FTA (2.260) > ThTA (2.154) > NapTA (2.054), ω (eV): NapTA (0.117) > ThTA (0.102) > BFTA (0.101) > PhTA (0.097) > FTA (0.090), ω⁺ (au): NapTA (0.060)> ThTA (0.048) > BFTA (0.047) > PhTA (0.044) > FTA (0.039), ω⁻ (au): NapTA (0.192) > BFTA (0.176) > ThTA (0.175) > PhTA (0.171) > FTA (0.162), ΔN_max (eV): NapTA (1.757) > ThTA (1.603) > BFTA (1.560) > PhTA (1.518) > FTA (1.472), ΔE_back-donat (eV): NapTA (−0.513) > ThTA (−0.538) > FTA (−0.565) > BFTA (−0.566) > PhTA (−0.573).

From Table 10, the PhTA compound preferred the intermolecular interactions more than the intramolecular charge transfer because the energy gap value was determined to be the highest in all simulation media, and vice versa for FTA. Moreover, the η, ω, ω⁺, ΔN_max, and ΔE_back-donat values of the compounds exhibited the same order in all solvents. However, the electronic chemical potential values (χ, eV) of the compounds were predicted as follows: χ (eV): FTA (−3.403) > ThTA (−3.532) > PhTA (−3.548) > BFTA (−3.553) > NapTA (−3.693) in gas, whereas χ order was determined in the order of FTA (−3.449) > BFTA (−3.580) > ThTA (−3.582) > PhTA (−3.592) > NapTA (−3.743) in chloroform. A similar order of the electronic chemical potential was estimated for the methanol and DMSO phases. Herein, the FTA could be less electronically stable among the compounds, and NapTA is the most stable electronically. Related to the electronic chemical potential, the differences between the gas phase and the other phases were that the BFTA compound was more stable than the PhTA and then the ThTA compounds, while the PhTA could be more stable than the ThTA and then the BFTA compounds. Accordingly, the results revealed that the PhTA compound was determined to be the hardest compound among the compounds, while NapTA was the softest. Furthermore, NapTA was the most electrophilic compound, while the FTA could be the least electrophilic compound. From Table 10, the NapTA compound had the highest charge transfer capability, while the FTA had the least charge transfer capability. Additionally, the PhTA compound gained the most stability via back-donation, among the compounds, and NapTA gained the least stability via back-donation, with the orders of NapTA (−0.507) > ThTA (−0.534) > FTA (−0.558) > BFTA (−0.563) > PhTA (−0.568) in gas and the orders of NapTA (−0.505) > ThTA (−0.532) > FTA (−0.557) > BFTA (−0.562) > PhTA (−0.567) in DMSO.

Moreover, the FMO densities and MEP plots showed the possible reactive sites and electron-rich and electron-poor regions for the electrophilic and nucleophilic attack reactions. Herein, Fig. 5 shows the FMO amplitudes and MEP plots of the compounds. In fact, the LUMO for all compounds expanded on the whole surface except for the –NH₂ group, while the HOMO exhibited different types of expansion on the related surfaces of the compounds. For instance, the HOMO for FTA and ThTA compounds was expanded on the whole molecular surface, while the LUMO, the HOMO for the BFTA compound was separated on the molecular surface except for the dihydrofuran unit, while the LUMO was delocalized on the whole surface except for the –O–C– atoms of the dihydrofuran unit. MO was separated on the molecular surface except for the –NH₂ group. Additionally, the HOMO of PhTA was separated on the whole thiazol-2-amine ring and benzene ring by more than half. The HOMO of the NapTA compound appeared on the mostly thiazol-2-amine ring and half on the naphthalene unit of the compound, while the LUMO of this compound was mostly observed on the naphthalene unit and the thiazol-2-amine ring half. As is well known, the HOMO is related to the possible sites for nucleophilic attacks, and the LUMO is associated with electrophilic attack sites. Accordingly, the –NH₂ group was not related to the electrophilic attack reactions due to the lack of LUMO density in this group. Moreover, the MEP plot of the PhTA compound implied that the Hs of the –NH₂ group would be a possible site for the nucleophiles because of these atoms bearing blue color (V > 0) as an indicator of the electron-poor region as a function of the electrostatic potential on the surface. Additionally, the red color (V < 0) for the PhTA compound appeared on the aromatic benzene ring, which was the electron-rich region. Furthermore, the –NH₂ group for the BFTA and FTA compounds would be a suitable region for the nucleophiles, while the O atom around, which was covered by red color, could be the proper site for the electrophiles. The color scheme of the MEP plots has provided a molecular insight into the possible active sites of the related molecules.

Fig. 5 HOMO and LUMO (isoval: 0.02) and MEP (isoval: 0.0004) plots.

3.6. Molecular docking analysis

Molecular docking is one of the most useful computational tools for predicting the binding modes and orientation of a molecule against a target biomacromolecule. In drug discovery research, the method can identify and optimize drug candidates and gain insight into the detailed structure of the protein–ligand complex, which generally is not available experimentally.⁹¹ In addition, molecular docking helps estimate how structural modifications in small molecules influence their pharmaceutical properties. Thus, this approach both accelerates drug discovery and provides valuable insights into the molecular interactions underlying various biological processes.⁹²

Angiogenesis refers to “the formation of new blood vessels from pre-existing ones”. Physiological angiogenesis occurs predominantly during growth until adolescence and proceeds at a much slower rate in adults, where it plays roles in processes such as wound healing and pregnancy. Additionally, under conditions such as inflammation, diabetic retinopathy, atherosclerosis, and tumor development, pathological angiogenesis arises. A major regulator of this process is vascular endothelial growth factor (VEGF).⁹³ The VEGF family consists of seven glycoproteins that exert biological activity by binding to specific transmembrane tyrosine kinase receptors, namely VEGFR-1, VEGFR-2, VEGFR-3, and neuropilins (NP-1 and NP-2). Among these, VEGFR-2 is of particular importance due to its key role in endothelial cell proliferation and migration. Consequently, VEGFR-2 represents a crucial therapeutic target for suppressing angiogenesis in cancer and other diseases. Several VEGFR-2 inhibitors have already been incorporated into cancer treatment strategies,⁹⁴ and research on the development of novel inhibitors is actively ongoing. For instance, Al-Hazmy et al. investigated coumarin derivatives for their antiproliferative potential through molecular docking studies against the VEGFR-2 crystal structure. Their analysis revealed hydrogen bonding interactions with Asn921 and Cys917, along with π-interactions involving Val914 and Leu1038.⁹⁵ Similarly, a benzimidazole-type N-heterocyclic carbene (NHC) and its silver complex were studied owing to their anticancer properties with both experimental and theoretical methods by Serdaroğlu et al. docking studies against VEGFR-2 showed that the silver complex exhibited stronger binding affinity (−7.59 kcal mol⁻¹) than its precursor salt, with key interactions with Asp1044, Glu883, Ile886, Val896, Cys1022, and His1024.⁹⁶ In another study, Pinki and Chaudhary analyzed novel macrocyclic Zn(II) complexes for their anticancer activity against breast and colon cancer cells. Their additional docking analyses using VEGFR-2 revealed hydrogen bonding with Lys866 in addition to hydrophobic interactions with Leu838, Cys917, Arg1030, and Asp1044.⁹⁷ In this study, molecular docking analysis was conducted to elucidate the potential mechanisms responsible for the anticancer activity of the synthesized compounds through their interactions with VEGFR-2. All compounds were found to bind within the same active site region of the target protein, displaying only minor differences in orientation. The interacting amino acid residues were largely consistent with those identified for the reference ligand, 4-amino-furo[2,3-d]pyrimidine (AAFP), and they agreed with previously reported findings. AAFP, employed as a positive control, exhibited a binding energy of −5.61 kcal mol⁻¹ and formed hydrogen bonds with Glu883, Glu915, Cys917, and Asp1044. The root mean square deviation (RMSD) values of the predicted binding poses were ≤2 Å, supporting the reliability and accuracy of the docking results. The best binding constant was determined for NapTA as −5.74 kcal mol⁻¹. H-bonds with Lys1021, Cys1022, and Ile1023, pi-interactions with Arg1025 and Asp1044, and alkyl interactions with Ile886, Ile890, and Leu1017 were determined in addition to van der Waals interactions with Val896, His1024, Ile1042, and Cys1043. PhTA, BFTA, FTA, and ThTA had binding affinities of −5.23, −5.52, −5.00, and −5.12 kcal mol⁻¹, respectively. H-bonds were recorded for all molecules: three H-bonds with Ile1023, His1024, and Asp1044 for PhTA; one H-bond with Glu883 for BFTA; two H-bonds with Ile1023 and His1024 for FTA; and three H-bonds with Ile1023, His1024, and Asp1044 for ThTA. All the interaction details are depicted in Fig. 6.

Fig. 6 Interaction residues and the interaction types of the molecules against the VEGFR-2 crystal structure (in 2D illustration, dark green and pale green: H-bond, pink: alkyl interactions, yellow: pi-sulfur interactions, green: van der Waals interactions, fuchsia: pi-amide stacked, purple: pi-sigma, and orange: pi-anion/cation).

Estrogen receptors (ERs) are specialized proteins for the mediation of the physiological effects of estrogen hormones and are members of the nuclear receptor superfamily. By binding to these receptors, estrogens regulate the maintenance and differentiation of nervous, reproductive, and skeletal tissues. Importantly, estrogen receptors can be expressed in many breast cancer tumors, and their growth is stimulated by estrogen. Consequently, modulation of ER activity represents a key therapeutic strategy in the treatment of breast cancer. Similar receptor-targeted approaches are also applied in the management of osteoporosis and certain cardiovascular diseases.⁹⁸ Several molecular docking studies have explored novel ligands for ER modulation. For example, Kumar et al. synthesized new quinoline derivatives with potential anticancer activity and evaluated their interactions with estrogen receptors. The docking scores ranged from −8.04 to −9.39 kcal mol⁻¹, with hydrogen bonding interactions identified at residues Thr347, Glu353, and Arg394.⁹⁹ Similarly, Sarkar and Maiti investigated the organosulfur and flavonoid components of garlic as potential ER-targeting agents. Among the flavonoids, kaempferol exhibited the most favorable binding affinity, with a score of −8.0 kcal mol⁻¹.¹⁰⁰ In a more recent study, several chlorogenic acid derivatives were examined by Sehrawat et al. using silico approaches. The most active ligand presented a hydrogen bond with Asp351, π-interactions with Tyr526, and hydrophobic interactions, highlighting its potential as a therapeutic candidate.¹⁰¹ In this study, a molecular docking analysis was performed against the human estrogen receptor. All compounds were found to bind within the same active site region of the target protein, displaying only minor differences in orientation. The interacting amino acid residues were largely consistent with those identified for the reference ligand, hydroxytamoxifen, and they agreed with previously reported findings. AAFP, employed as a positive control, exhibited a binding energy of −10.35 kcal mol⁻¹ and formed hydrogen bonds with Asp351, Glu353, and Arg394. The root mean square deviation (RMSD) values of the predicted binding poses were ≤2 Å, supporting the reliability and accuracy of the docking results. The best binding constant was determined for NapTA as −6.58 kcal mol⁻¹. H-bond with Glu323; pi-interactions with Glu353, Met357, Trp393, Arg394, and Lys449; and alkyl interactions with Pro324 and Leu387 were determined in addition to van der Waals interactions with Ile326, His356, Ile386, Gly390, and Phe445. PhTA, BFTA, FTA, and ThTA had binding affinities of −5.53, −5.97, −5.09, and −5.09 kcal mol⁻¹, respectively. H-bonds were recorded for all molecules: one H-bond with Lys449 for PhTA; five H-bonds with Glu323, Pro324, Glu353, Leu387, and Arg394 for BFTA; five H-bonds with Glu323, Glu353, Leu387, Arg394, and Lys449 for FTA; and two H-bonds with Glu323 and Lys449 for ThTA. All the interaction details are presented in Fig. 7.

Fig. 7 Interaction residues and the interaction types of the molecules against the estrogen receptor crystal structure (in 2D illustration, dark green and pale green: H-bond, pink: alkyl interactions, yellow: pi-sulfur interactions, green: van der Waals interactions, fuchsia: pi-amide stacked, and purple: pi-sigma).

Cytochrome P450 (CYPs) constitutes a large enzyme superfamily responsible for the metabolism of various xenobiotics, such as drugs, industrial chemicals, and pesticides. In addition to these external compounds, several endogenous molecules such as prostaglandins, steroids, and fatty acids also serve as physiological substrates for CYP enzymes.¹⁰² Alterations in the expression levels of CYPs, often resulting from gene polymorphisms or structural variations, can significantly influence xenobiotic metabolism, thereby affecting tolerance to these compounds. Among the CYP family, P450 17α-hydroxylase plays a critical role in androgen biosynthesis in humans, making it an important therapeutic target in the treatment of ovarian, colorectal, breast, and prostate cancers.¹⁰³ Several molecular docking studies have been conducted to identify potential CYP inhibitors with anticancer properties. For instance, Dhawale et al. evaluated the interactions of various phytoconstituents with CYP450 and reported strong binding affinities for peonidin, pelargonidin, malvidin, and berberine, with the best affinity recorded at −7.574 kcal mol⁻¹ through notable hydrogen bonding interactions.¹⁰⁴ Similarly, Bahzad et al. investigated novel Cu(II) complexes with mixed ligands for anticancer potential. Molecular docking against CYP450 revealed binding affinities ranging from −5.60 to −7.91 kcal mol⁻¹.¹⁰⁵ In another study, Tajiani et al. performed molecular docking of natural flavanols against the CYP450 crystal structure in a PC-3 cell line model. Abiraterone displayed the most favorable binding profile, with an affinity of −10.3 kcal mol⁻¹, forming interactions with residues Val483, Glu305, Arg239, and Cys442.¹⁰⁶ In this study, the aminothiazole-type molecules were analyzed to reveal their interactions with human cytochrome P450 using molecular docking methods. All molecules interacted with the same area of the target crystal, which is in accordance with abiraterone (the reference molecule). The root mean square deviation (RMSD) values of the predicted binding poses were ≤2 Å, supporting the reliability and accuracy of the docking results. The best binding constant was determined for NapTA as −6.83 kcal mol⁻¹. H-bond with Ala367, pi-interactions with Val366, Pro434, Phe435, and Cys442, and alkylic interactions with Val310, and Ala448 were determined in addition to van der Waals interactions with Thr306, Leu361, Pro365, Leu370, Leu396, Gly436, and Leu452. PhTA, BFTA, FTA, and ThTA had the following binding affinities: −5.48, −6.24, −4.70, and −5.10 kcal mol⁻¹, respectively. H-bonds were recorded for all molecules: three H-bonds with Gly303, Thr306, and Glu451 for PhTA; four H-bonds with Gly303, Thr306, Pro434, and Glu451 for BFTA; four H-bonds with Gly303, Thr306, Cys442, and Glu451 for FTA; and four H-bonds with Gly303, Thr306, Cys442, and Glu451 for ThTA. All the interaction details are depicted in Fig. 8.

Fig. 8 Interaction residues and the interaction types of the molecules against the cytochrome P450 crystal structure (in 2D illustration, dark green and pale green: H-bond, pink: alkyl interactions, yellow: pi-sulfur interactions, green: van der Waals interactions, fuchsia: pi-amide stacked, grass green: pi-lone pair, and purple: pi-sigma).

Mitogen-activated protein kinases (MAPKs) are a group of protein kinases that play an important role in signaling pathways for responding to extracellular stimuli, such as growth factors, hormones, and environmental stresses. Extracellular signal-regulated kinase 2 (ERK2) is one of the isoforms of this kinase family. ERK2 plays an important role in regulating cell proliferation, differentiation, and survival, as well as gene expression.¹⁰⁷ Dysregulation of the ERK signaling pathway is associated with various diseases, including cancer and neurodegenerative disorders. Small ERK2 inhibitors are considered recent potential anticancer drugs.¹⁰⁸ Zhao et al. investigated the inhibitory activities of 20(R, S)-PPT and confirmed their results using molecular docking methods against some target proteins, including ERK2.¹⁰⁹ Niu et al. discussed the binding mechanism of pyrrolidine piperidines using molecular docking techniques and provided valuable information for efficient Type I1/2 ERK2 inhibitors.¹¹⁰ In this study, the aminothiazole-type molecules were analyzed to reveal their interactions with ERK2 by applying molecular docking methods. All molecules interacted with the same area of the target crystal, which is in accordance with SCH772984 (the reference molecule). The root mean square deviation (RMSD) values of the predicted binding poses were ≤2 Å, supporting the reliability and accuracy of the docking results. The best binding constant determined for PhTA was −6.08 kcal mol⁻¹. H-bonds with Asp149, Thr190, and Arg194, pi-interactions with Arg148, Tyr193, and Ser213, and alkylic interactions with Lys151 and Ile209 were determined in addition to van der Waals interactions with Leu150, Arg191, Ala195, Ile198, and Asp210. BFTA, FTA, ThTA, and NapTA had binding affinities of −5.22, −5.95, −6.03, and −5.16 kcal mol⁻¹, respectively. H-bonds were recorded for all molecules: four H-bonds with Arg148, Ile209, Asp210, and Ser213 for BFTA; five H-bonds with Asp149, Leu150, Thr190, Arg194, and Asp210 for FTA; two H-bonds with Asp149 and Thr190 for ThTA; and four H-bonds with Arg148, Ile209, Asp210, and Ser213 for NapTA. All the interaction details are illustrated in Fig. 9.

Fig. 9 Interaction residues and the interaction types of the molecules against the ERK2 crystal structure (in 2D illustration, dark green and pale green: H-bond, pink: alkyl interactions, yellow: pi-sulfur interactions, green: van der Waals interactions, fuchsia: pi-amide stacked, and grass green: pi-lone pair).

4. Conclusions

In conclusion, we have demonstrated a novel and efficient synthesis of 2-aminothiazole derivatives using iodine and molecular sieves derived from various ketones. This innovative approach aligns with ongoing efforts in green chemistry and emphasizes the importance of developing greener alternatives for sustainable chemical processes. The use of readily available starting materials, high selectivity, and mild reaction conditions makes this method particularly attractive. Additionally, aminothiazole-type molecules were evaluated for their inhibition effect against VEGFR-2, estrogen receptor, cytochrome P450, and ERK2 using the molecular docking method. NapTA has the best binding affinity against VEGFR-2, estrogen receptor, and cytochrome P450 with −5.74, −6.58, and −6.83 kcal mol⁻¹ binding affinity, respectively, while the strongest interactions were recorded between ERK2 and PhTA with a −6.08 kcal mol⁻¹ binding constant. All the molecules had H-bonds against all target molecules, and the interaction residues were in accordance with the reference molecules. Accordingly, aminothiazole derivative molecules should be evaluated for these biomacromolecules. In future studies, new polycyclic substitutions should be a remarkable way to investigate possible inhibitor effects.

Author contributions

Goncagül Serdaroğlu: supervision, project administration, formal analysis, writing – review & editing. Nesimi Uludağ: validation, formal analysis, resources, writing – review & editing. Elvan Üstün: validation, formal analysis, resources, writing – review & editing.

Conflicts of interest

No conflicts of interest to be declared.

Data availability

Data are available in the manuscript and the supplementary information (SI). Supplementary information is available. See DOI: https://doi.org/10.1039/d5ra09930g.

Acknowledgements

Financial support for this research was received from the Scientific and Technological Research Council of Turkey (TUBITAK Project No. 112T503). The authors thank Namık Kemal University for the analysis of the structure of this article. All calculations have been carried out at the TUBITAK ULAKBIM, High Performance and Grid Computing Center (TR-Grid e-Infrastructure).

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