A two-decade overview of oxadiazole derivatives as promising anticancer agents

Abstract

One of the most difficult illnesses that people today must deal with is cancer. It is distinguished by aberrant cell division and growth, which results in the development of tumors and lumps. The heterocyclic nucleus has drawn a lot of interest in the field of chemotherapeutics; moreover, it is essential in medicinal chemistry. Oxadiazole is a nitrogen–oxygen heterocyclic core with five members that exhibits remarkable anticancer properties. Inhibiting different enzymes and growth factors is the mechanism linked to tumor defeat. This review has covered research conducted over the past 20 years as well as their potential applications in drug development as antineoplastic agents, given the significance of oxadiazole and its derivatives in this global panic problem. This review aims to highlight the anticancer properties of 1,3,4-oxadiazole and its derivatives, 1,2,4-oxadiazole.

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1 Introduction

The growth of abnormal cells that divide uncontrollably and have the ability to invade and destroy healthy body tissues is what defines cancer.¹ One of the most challenging public health issues facing humanity is cancer, which is characterized by high rates of morbidity and mortality.¹ Since cancer accounts for three out of ten premature non-communicable diseases (NCD)-related deaths globally (30.3% in individuals aged 30 to 69 years), it is primarily responsible for one in four deaths (22.8%).² Female breast cancer was the second most common type of cancer in 2022, accounting for 2 308 897 new cases with a death of roughly 665 684, while liver cancer was responsible for about 865 269 new cases with a death of roughly 757 948.² In 2023, about 1 958 310 new cancer cases, and about 609 820 deaths were recorded in USA for both males and females.³

Native Americans and Alaskans are more likely to develop hepatic cancers, whereas Europeans are more likely to develop female breast cancer.⁴ Oxadiazoles are heterocyclic compounds with a five-membered ring that have two nitrogen atoms and one oxygen atom.⁵ Oxadiazole can be made from furan by substituting two methane (–CH=) groups with two pyridine type nitrogen (–N=) groups. Oxadiazole has four structural isomers: 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, and 1,3,4-oxadiazole. Its nucleus has a mesomeric effect, which makes it a relatively weak base.^5,6 In addition to other pharmacological effects, imidazole, benzothiazole, benzimidazole, 1,3,4-oxadiazole, and 1,2,4-oxadiazole derivatives have been reported to exhibit cytotoxic and anticancer bioactivity.^6–8 Commercially available oxadiazole-based medications include the well-known anticancer zibotentan 1, butalamine 2, ataluren 3, oxolamine 4, and proxazole 5.⁹ With eight oxadiazole-based drug molecules approved by the US FDA and more in clinical trials, oxadiazole has a promising future in the drug discovery process for chemotherapy.^10,11

2 Material and methods

2.1 Data collection

Using electronic databases such as PubMed, Embase, and PsycINFO, a comprehensive literature search was carried out. “Oxadiazole nucleus”, “chemotherapy”, “therapeutic strategies”, “cancer cell lines” and “cancer” were the search terms used. To reflect the latest advancements, articles released from January 2005 to January 2025 were included. Preclinical and clinical researchs were taken into account.

2.2 Study selection

Complete texts of articles that might be of interest were obtained and their eligibility was evaluated. Studies concentrating on oxadiazole-based compounds with acceptable activity against different types of cancer are eligible to be included.

Exclusion criteria include articles written in languages other than English and studies that are not specifically about molecules based on oxadiazole moiety.

2.3 Data analysis

The extracted information was combined and subjected to a thematic analysis. The included studies' similarities and differences were noted. The main conclusions were outlined, emphasizing the benefits and drawbacks of various therapeutic modalities. Future directions and emerging trends were discussed.

2.4 Ethical considerations

Because this review article is based on the analysis and interpretation of previously published studies, ethical approval was not necessary.

2.5 Limitations

The quality and accessibility of the included studies place restrictions on the review. The review's focus is on oxadiazole-based compounds as anticancer agents; it ignores other topics like pathophysiological mechanisms or diagnostic techniques.

3 Results and discussion

Numerous derivative medications with an oxadiazole core have demonstrated clear cytotoxic and anticancer effects on various human cancer cell lines, including the following.

3.1 MCF-7 cell line

In 2021, several oxadiazole-based drugs were synthesized, including compound 1 (Fig. 1), which demonstrates anticancer activity against human breast cancer MCF-7 cell line, with an IC₅₀ value of 5.897 ± 0.258 μM.⁹ Compounds 2 and 3 (Fig. 1) exhibit potential as anticancer agents, with IC₅₀ values against MCF-7 of 15.708 ± 0.659 and 15.063 ± 0.728 μM, respectively.⁹ Substituting R₁ and R₂ in the original structure of the synthesized oxadiazole derivatives compounds 4(a–g) (Fig. 1) with various substituents such as H, Cl, CH₃, OCH₃, CN, and F resulted in the synthesis of a series of oxadiazole-containing compounds, these compounds were evaluated for anticancer activity, yielding IC₅₀ values ranging from 18.305 to 45.438 μM.⁹

Fig. 1 Compounds (1–6).

In 2021, Alam et al. synthesized a series of naproxen 1,3,4-oxadiazole derivatives, compound 5 (Fig. 1) exhibits a cytotoxic effect against MCF-7, with an IC₅₀ value of 2.13 μg mL⁻¹.¹² In the same year, Almalki et al. synthesized a series of 1,2,3-triazole-thymol-1,3,4-oxadiazole derivatives, compound 6 (Fig. 1) demonstrating the highest potency, this compound exhibited an antiproliferative effect against various human cell lines, with an IC₅₀ value of approximately 1.1 μM against MCF-7.¹³ In 2022, Kotla et al. synthesized a series of anticancer oxadiazole structures by substituting the R group in the structural formula depicted in compounds 7(a–e) (Fig. 2).¹⁴ Compound 7b (Fig. 2) exhibits anticancer activity against various human cell lines with an IC₅₀ of 0.31 μM for MCF-7.¹⁴ Sreenivasulu et al.¹⁵ synthesized two highly active oxadiazole-based drugs by substituting the R group in compounds 8(a and b) (Fig. 2).

Fig. 2 Compounds (7–12).

Compound 8a (Fig. 2) exhibits cytotoxicity against various human carcinoma cell lines, with an IC₅₀ of 1.8 μM against MCF-7. In contrast, Compound 8b (Fig. 2) demonstrates a cytotoxicity with an IC₅₀ of 2.6 μM against MCF-7.¹⁵ Abbas et al. created structures containing oxadiazole rings and assessed their anticancer activity against MCF-7 cells, compound 9 (Fig. 2) exhibited notable anti-tumor activity, evidenced by a GI₅₀ value of 86.8 mg mL⁻¹ against MCF-7 cells.¹⁶ Omar et al. synthesized drugs derived from 1,3,4-oxadiazole in an in vitro study, the cytotoxicity results indicate that compounds 10 and 11 (Fig. 2) demonstrated greater inhibitory effects on MCF-7 cells better than Doxorubicin 12 (Fig. 2), with IC₅₀ values of 1.76 ± 0.08 mM and 1.18 ± 0.04 mM, respectively.¹⁷ El-Etrawy and Sherbiny performed two sequential studies that led to the synthesis of two compounds, compound 13 (Fig. 3), a thiouracil derivative, exhibits significant anticancer activity against the MCF-7 cell line, with an IC₅₀ value of 3.80 microg per mL.¹⁸

Fig. 3 (13–18).

Compound 14 (Fig. 3) demonstrated a significant cytotoxic effect on MCF-7, with an IC₅₀ of 3.50 microg per mL. Doxorubicin 12 (Fig. 2), with an IC₅₀ of 2.97 microg per mL, was served as a control in this study.¹⁹ El-Mansouri et al. synthesized a series of 1,3,4-oxadiazole derivatives, and the cytotoxic activity of all synthesized compounds was evaluated in vitro against MCF-7, compound 15 (Fig. 3) demonstrates a significant growth inhibitory effect.²⁰ Mohan et al. detailed the synthesis of 1,2,4-oxadiazole-1,2,3-triazole-pyrazole derivatives and evaluated their anti-cancer activity against several cell lines, including MCF-7 cells. Compound 16 (Fig. 3) exhibited an IC₅₀ of 0.081 ± 0.0012 mM in its anticancer action against MCF-7 cells.²¹ Compounds 17 and 18 (Fig. 3) exhibited the highest levels of cytotoxicity, with IC₅₀ values ranging from 0.88 to 8.37 μM against several cell lines, including MCF-7.²² Furthermore, these compounds exhibited greater activity against MCF-7 cells compared to the reference, Doxorubicin 12 (Fig. 2).²² Compound 19 (Fig. 4) has emerged as a potential agent against the MCF-7 cell line, exhibiting an IC₅₀ of 5.704 ± 0.254 mm. A series of drugs derived from oxadiazole are synthesized by disubstitution as compounds 19–23 (Fig. 4). Among these, five structures exhibit significant anti-cancer effects, whereas the other structures demonstrate minimal anti-cancer activity against MCF-7.⁸ Compounds 20 (Hoechst 33342), 21, 22, 23 (Fig. 4) and (Doxorubicin) 12 (Fig. 2) exhibit notable cellular toxicity in MCF-7 cells with IC₅₀ values of 2.404 ± 0.118, 6.442 ± 0.287, 7.318 ± 0.352, 9.148 ± 0.391, and 10.525 ± 0.118 μM, respectively.⁸ Moreover, the oxadiazole hybrid propanamide 24 (Fig. 4) served as a selective inhibitor of HDAC8.¹¹

Fig. 4 Compounds (19–24).

IC₅₀ values against the breast cancer MDA-MB231 and MCF-7 cell lines decreased, demonstrating a dose-dependent effect alongside a reduction in the percentage of apoptotic cells and mitochondrial membrane potential.¹¹ A range of hybrid compounds integrating 1,3,4-oxadiazole and 1,3,4-thiadiazole with the Schiff base moiety were synthesized and evaluated in vitro for anticancer efficacy against SMMC-7721, MCF-7, and A549 human cell lines utilizing the CCK-8 assay,¹² The findings indicated that certain chemicals exhibited greater efficacy against various cell lines compared to the positive control, 5-fluorouracil (compound 25) (Fig. 5).

Fig. 5 Compounds (25–30).

Compound 26 (Fig. 5), exhibited the highest potency against SMMC-7721 cells, with an IC₅₀ value of 2.84 μM.²³ Compounds 27 and 28 exhibited significant anticancer activity against MCF-7 cells, with IC₅₀ values of 4.56 μM and 4.25 μM, respectively²³ (Fig. 5). The unsubstituted phenyl compound 29 (Fig. 5) and the 4-nitro-substituted Compound 28 (Fig. 5) demonstrated significant efficacy against A549 cells, with IC₅₀ values of 4.11 μM and 4.13 μM, respectively.²³ The pharmacological findings demonstrate that substituents on the phenyl ring of 1,3,4-oxadiazole play a significant role in altering antiproliferative effects across various tumor cell lines.²³

In 2015, various oxadiazole derivatives were examined for their antiproliferative effects in four distinct human cancer cell lines: MCF-7, T47D, Caco-2 and HeLa cells.²⁴ Every chemical showed comparatively high activity against the cell lines under investigation. While converting the methyl and phenyl groups in compound 30a,c (Fig. 5) and compound 31a,c (Fig. 6) into ethyl groups 30b (Figure 5) and 31b (Fig. 6) significantly increased the cytotoxic activity with LD₅₀ values ranging from 376 ng per microL to 438 ng per microL, there was no difference in activity associated with replacing oxadiazole with thiadiazole.^24,25 This suggests a steric factor mediating either transport or molecular interaction of these compounds with cellular targets. Additionally, compound 32b (Fig. 6), which has twice the activity (LD₅₀ = 356–398), was created by adding one additional Cl atom to structure 32a (Fig. 6) (LD₅₀ = 648–690).²⁴

Fig. 6 Compounds (31–35).

Sun et al. (2013) identified and examined 1,3,4-oxadiazole compounds containing quinoline groups, the study involved testing three distinct cancer cell lines: HepG2, (SGC-7901), and MCF-7.²⁶ Compounds 33 and 34 (Fig. 6) exhibited anti-proliferative effects with IC₅₀ values of 7.1 and 6.8 μM, respectively against MCF-7 which are greatly higher than 5-fluorouracil 25 (Fig. 5). The telomerase inhibitory activity exhibited by them was significantly greater than that of the reference Staurosporine 35 (Fig. 6).²⁶ In 2014, Zhang et al. examined the inhibitory effects of pyridine 1,3,4-oxadiazole analogues on telomerase activity.²⁷ Among the derivatives obtained, compound 36 (Fig. 7) demonstrated the most potent anti-cancer activity against four distinct cancer cell lines: liver cancer HePG2, MCF-7, SW1116, and BGC823, surpassing the efficacy of the reference compound, 5-fluorouracil 25 (Fig. 5).²⁷

Fig. 7 Compounds (36–41).

Compound 36 (Fig. 7) exhibited significant inhibitory potential against telomerase enzyme, exceeding that of the comparator medication, Staurosporine 35 (Fig. 6).²⁷ Thasneem et al. developed a series of chalcone-linked oxadiazole derivatives by synthesizing various substituted chalcones with substituted oxadiazole. These derivatives were evaluated for anticancer activity against MCF-7 cell line using the MTT assay, compound 37 (Fig. 7) exhibits significant activity, with an IC₅₀ of 6.8 μM.²⁸

Kamal et al. developed a restricted library of hybrids containing oxadiazole to evaluate their antineoplastic activity in vitro on several human cell lines, including IMR32, HeLa, MCF-7, and A549. Three produced hybrids, 38a, 38b, and 38c (Fig. 7), demonstrated significant cytotoxicity against the specified human cell types and inhibited tubulin polymerization.²⁹ A molecular docking study was performed to elucidate the mechanisms by which effective derivatives interact with the active colchicine site. IC₅₀ values for cytotoxicity range from 1.5 to 11.2 μM, while values for tubulin polymerization inhibition are 1.3, 3.9, and 2.4 μM.²⁹

Rahman presented findings on the anticancer activity and QSAR studies of a series of 2,5-disubstituted-1,3,4-oxadiazole, 2-substitutedthio-5-substituted-1,3,4-oxadiazole, and Mannich bases of 5-substituted-1,3,4-oxadiazole-2(3H)-thione featuring a diphenylamine moiety.³⁰ The Sulfo-Rodamine B (SRB) assay was employed to evaluate the antiproliferative activity of all synthesized compounds against MCF-7 and HT29 cancer cell lines.³⁰

Compared to the MCF-7 cell line, all tested drugs exhibit significant antiproliferative effects on human colon cancer HT29 cells. Compounds (39–43) (Fig. 7 and 8) exhibited significant cytotoxicity (IC₅₀ 1.3–2.0 μM) towards the HT29 cell line. QSAR analysis indicates that the steric bulk of a molecule's structure and conformation is a critical factor in anticancer efficacy.³⁰

Fig. 8 Compounds (42–47).

A series of 2,5-disubstituted-1,3,4-oxadiazoles featuring amide, urea, and sulphonamide functionalities has been reported.³¹ 15 Compounds were synthesized and evaluated for anticancer activity, among them compound 44 (Fig. 8) has been identified as an effective anticancer agent.³¹ The structure–activity relationship (SAR) of synthesized compounds indicated that the presence of a urea moiety with an electron-donating group enhances cytotoxicity. Additionally, the incorporation of substituted benzene sulphonamide into the 1,3,4-oxadiazole ring increased cytotoxicity against the MCF-7 cell line.

Conversely, the attachment of a substituted benzamide unit to 1,3,4-oxadiazole derivatives diminished cytotoxicity against both the MCF-7 and HeLa cell lines.³¹ Selvaraj et al. demonstrated that the incorporation of electron-donating groups at the p-position of urea and sulphonamide units containing 1,3,4-oxadiazole rings enhanced anticancer activity.³¹ Subramanyam et al. synthesized ten 1,3,4-oxadiazole-2-benzothiazole derivatives featuring five aryl substitutions.³² Ravinaik et al. synthesized a series of amide 1,3,4-oxadiazole linked benzoxazole derivatives, with their structures validated by spectral data.³³ The synthesized compounds were evaluated against four human cancer cell lines: A549, MCF-7, A375, and HT-29, using Combretastatin-A4 45 (Fig. 8) as a control medication.³³ Compound 46 and 47 (Fig. 8) exhibited superior anticancer activity against the HT-29 cancer cell line when compared to the standard medication, with IC₅₀ values of 0.018 and 0.093 μM, respectively.³³

Zhang and colleagues synthesized a series of oxadiazole rings integrated into a steroid framework.³⁴ Two of these compounds 48 and 49 (Fig. 9) exhibited anti-proliferative effects on four cell lines (HepG2, MCF-7, A549, and HCT-116).³⁴

Fig. 9 Compounds (48–53).

Bhat et al. synthesized oxadiazole derivatives, compounds 50 and 51 (Fig. 9), demonstrated notable efficacy against the breast cancer MCF-7 cell line.³⁵

Sun et al. synthesized 1,3,4-oxadiazole possessing 1,4-benzodioxan moiety. Most of the synthesized derivatives were evidenced to have powerful antitumor activities and low toxicities. Amongst them, compounds 52 and 53 (Fig. 9) displayed the greatest anticancer activities against Human Umbilical Vein Endothelial cells.³⁶

Puthiyapurayil et al. synthesized various oxadiazole compounds incorporating the N-methyl-4-(CF₃) phenyl pyrazole moiety.³⁷ One compound exhibited the highest cytotoxic activity with MIC value of 15.54 mm in MCF-7 cells, identified as compound 54 (Fig. 10).³⁷ Liu et al. developed a series of 2-(benzylthio)-5-aryloxadiazoles, one of these derivatives (compound 55) demonstrated significant anti-tumor effects in tests conducted on cell lines including MCF-7, A549, and B16-F10.³⁸ Gefitinib was utilized as the reference drug for comparison.³⁸

Fig. 10 Compounds (53–59).

Bondock et al. presented various heterocyclic structures associated with oxadiazole. Five compounds demonstrated significant efficacy against HepG2, WI 38, MCF-7, and VERO at MIC concentrations between 10 and 1000 μg mL⁻¹, particularly compounds 56 and 57 (Fig. 10) displayed 32.6 and 37.4 μg mL⁻¹ against MCF-7, respectively.³⁹

Kumar et al. proposed a series of 1,2,4-oxadiazole derivatives.⁴⁰ The trichloromethyl analogs exhibited the highest efficacy among the derivatives in this series, showing notable activity against PC3, DU145, LnCaP, MCF-7, MDA-MB-231, PaCa2, and DUP145, specially compound 58 (Fig. 10).⁴⁰

Lakshmithendral et al. synthesized 2-(phenoxymethyl)-5-phenyl-1,3,4-oxadiazoles.⁴¹ Two analogs demonstrated moderate to strong anti-breast cancer activity in the MDA-MB-453 and MCF-7 cell lines, specifically compounds 59 and 60 (Fig. 10 and 11).⁴¹ Du et al. identified 1,3,4-oxadiazole-thioether derivatives as inhibitors of the thymidylate synthase enzyme, demonstrating their potential as anti-cancer agents. Compound 61 (Fig. 11) demonstrated the highest efficacy, exhibiting IC₅₀ values of 0.7 μM, 18.3 μM, and 30.0 μM against HepG2, MCF-7, and SGC-7901 cancer cell lines, respectively.⁴²

Fig. 11 Compounds (60–65).

Derivatives of 1,3,4-oxadiazole and thiazolidine-2,4-dione, particularly compound 62 (Fig. 11) exhibited notable cytotoxic activity, with IC₅₀ values between 0.81 and 11.9 μM against A549, A375, MCF-7, and HT-29 cancer cell lines.^43,44 Alzhrani et al. reported on hybrids of 1,3,4-oxadiazole and thiazolidinedione, specifically compound 63 and 64 (Fig. 11), which demonstrated cytotoxicity with IC₅₀ values of 7.74 and 7.87, respectively, against the MCF-7 cell line through the inhibition of the thymidylate synthase enzyme.⁴⁴

Compound 65 (Fig. 11), which contains both 1,3,4-oxadiazole and 1,2,4-oxadiazole structures, demonstrated significant anticancer activity with IC₅₀ values ranging from 0.34 to 2.45 μM against MCF-7, A549, and MDA-MB-231 cancer cell lines through the inhibition of EGFR (epidermal growth factor receptor).⁴⁵ Jisha et al. synthesized compound 66 (Fig. 12), demonstrating significant cytotoxicity against DLA and MCF-7 with LD₅₀ values of 136 μg mL⁻¹ and 132 μg mL⁻¹, respectively.⁴⁶

Fig. 12 (66–71).

Kapoor and Dhiman synthesized compound 67 (Fig. 12), which exhibited notable cytotoxic effects against MCF-7 cells.⁴⁷ Abdo and Kamel reported a series of compounds 68, 69 and 70 (Fig. 12), which exhibited cytotoxic effects between 0.725 and 3.274 μM across six human cancer cell lines: NUGC, DLD1, HA22T, HEPG2, HONE1, and MCF-7 cells.⁴⁸ Slawinski et al. synthesized compound 71 (Fig. 12) that has demonstrated promising anti-cancer activity against HCT-116, MCF-7, and HeLa cancer cell lines, with an IC₅₀ value between 11 and 29 μM.⁴⁹ The ibuprofen derivative (compound 72) (Fig. 13), was reported by Alderawy et al.,⁵⁰ and exhibited significant cytotoxicity, attaining 85.1% inhibition of MCF-7 cells. Malojirao et al. synthesized compound 73 (Fig. 13), as a potent cytotoxic agent, demonstrating IC₅₀ values ranging from 4.8 to 5.1 μM against A549, MCF-7, A375, HepG2, Huh-7, ACHN, A498, and LLC cells.⁵¹ Moreover, derivatives of benzopyran 1,3,4-oxadiazole, developed by Kumar et al., demonstrated significant anti-cancer effects on the MCF-7 cell line.⁵² Derivatives of resveratrol-linked 1,3,4-oxadiazole, specifically compounds 74 and 75 (Fig. 13), demonstrated improved anti-cancer efficacy, with IC₅₀ values of 0.11 μM to 1.56 μM and 0.45 μM to 1.98 μM, respectively, in comparison to the standard drug Adriamycin (Doxorubicin) 12 (Fig. 2) which exhibited IC₅₀ values ranging from 2.10 μM to 3.41 μM against MCF-7, A549, and MDA-MB-231 cells.⁵³ Innovative pyrimidine-oxazole based 1,3,4-oxadiazole hybrids, compound 76 (Fig. 13), demonstrated significant anti-cancer activity with IC₅₀ values ranging from 0.011 μM to 19.4 μM. In comparison, the reference drug etoposide compound 77 (Fig. 13) exhibited IC₅₀ values from 0.13 μM to 3.08 μM against MCF-7, A549, Colo-205, and A2780 cell lines.⁵⁴

Fig. 13 Compounds (72–77).

3.2 HepG2 CELL LINE

Gold et al. (2016) developed a cephalosporin analogue that exhibits a significant activity against the human liver cancer HepG2 cell line, with an LD₅₀ greater than 100 g mol⁻¹ for compound 78 (Fig. 14).⁵⁵

Fig. 14 Compounds (78–81).

Compound 5 (Fig. 1) demonstrates notable cytotoxicity against the HepG2 cell line, exhibiting an IC₅₀ value of 1.63 μM, among the series of naproxen 1,3,4-oxadiazole derivatives developed by Alam et al..¹² Compound 6 (Fig. 1), a drug synthesized by Almalki et al. that combines 1,2,3-triazole with thymol-1,3,4-oxadiazole, exhibits a proliferation inhibitory effect against HepG2 hepatic cancer with an IC₅₀ of 1.4 μM. This efficacy surpasses that of the established drugs Doxorubicin 12 (Fig. 2) and 5-fluorouracil 25 (Fig. 5), which have IC₅₀ values of 1.8 μM and 28.65 μM, respectively, against HepG2.¹³

A series of indazole tethered oxadiazole compounds were synthesized by Dukanya et al., compounds 79a, 79b, 79c, and 79d (Fig. 14) exhibited anticancer activity against human liver cancer HepG2, with IC₅₀ values of 19.5, 21.4, 24.5, and 22.3 μM, respectively.⁵⁶ In vitro studies demonstrated that compound 79a inhibited the proliferation of HepG2 cells through the suppression of SIRT2 expression.⁵⁶ The anticancer activity of compounds 80a, 80b, and 80c (Fig. 14) were evaluated on HepG2 by Kaneko et al. The group of derived 1,2,4-triazole[4,3-a] quinoxaline-1,3,4-oxadiazole molecules exhibits IC₅₀ values against HepG2 of (5.35 ± 0.22), (4.86 ± 0.25), and (3.84 ± 0.13 μM), respectively.⁵⁷ Compounds 81a and 81b (Fig. 14) exhibited cytotoxic activity against HepG2, measured at 5.695 ± 0.283 μM and 21.86 ± 0.991 μM, respectively, superior to Doxorubicin compound 12 (Fig. 2).⁸

Compounds 82 and 83 (Fig. 15) exhibited notable anticancer efficacy with IC₅₀ values of 7.21 μM and 8.54 μM, respectively, against HepG2.⁵⁸ Additionally, compounds 84 and 85 (Fig. 15) demonstrate IC₅₀ values of 4.22 μM and 5.79 μM, respectively, surpassing the positive control Staurosporine 36 (Fig. 7) (IC₅₀ = 6.73 μM).⁵⁹ Sun et al. synthesized a series of 1,3,4-oxadiazole-based candidates, including compounds 33 and 34 (Fig. 6), which exhibited higher HepG2 antiproliferative activity than 5-fluorouracil 25 (Fig. 5), with IC₅₀ values of 0.8 ± 0.2 and 1.2 ± 0.2 μM, respectively (5-fluorouracil IC₅₀ = 21.9 ± 1.4 μM).²⁶

Fig. 15 Compounds (82–85).

Yang et al. developed a series of 1,2,4-oxadiazole-based drug derivatives, including compounds 86 and 87 (Fig. 16), which exhibit IC₅₀ values of 1.07 μM and 1.03 μM against HepG2, respectively.⁶⁰

Fig. 16 Compounds (86 and 87).

Bhat et al. synthesized compound 88 (Fig. 17) that demonstrated significant cytotoxic effects, with an IC₅₀ value of 0.26 μM against the HepG2 cell line, through the inhibition of EGFR and cyclin-dependant kinase CDK2 activity.⁶¹ Compound 89 (Fig. 17) exhibited promising anticancer activity against the HepG2 cell line in comparison to 5-fluorouracil 25 (Fig. 5).⁶² Compound 90 (Fig. 18) exhibits the highest efficacy in inhibiting the growth of liver cancer cells (HepG2) relative to the reference, 5-fluorouracil (compound 25) (Fig. 5).⁶²

Fig. 17 Compounds (88–91).

Fig. 18 Compounds (92–97).

Madhavilatha et al. furnished a derivative of 1,2,3-triazole or isoxazole linked to 1,3,4-oxadiazole, as a potential anticancer agents. These derivatives were evaluated for their antineoplastic properties in vitro against four human cell lines: HeLa, MDA-MB-231, DU-145, and HEPG2, representing cervical, breast, prostate, and liver cancers, respectively.⁶³

Compounds 91a–c (Fig. 17) disrupts the cell cycle at the G2/M phase and acts as an inhibitor of tubulin polymerization.^63,64

Compounds 91a, 91b, and 91c (Fig. 17) exhibited notable anticancer activity. The growth inhibition (GI₅₀) values for the respective cell lines in μM were 1.28, 1.75, 2.39, and 1.84 for 91a; 1.7, 2.14, 1.72, and 1.78 for 91b; and 0.82, 1.04, 0.96, and 1.42 for 91c, respectively.⁶³

The anti-cancer properties of 1,3,4-oxadiazole-thioether derivatives were assessed using three distinct cell lines: HepG2 for liver cancer, SGC-7901 for stomach cancer, and MCF-7 for breast cancer. Compound 61 (Fig. 11) exhibits the most significant activity against liver cancer cells, demonstrating an effect 30 times greater than that of the reference drug, 5-fluorouracil 25 (Fig. 5).^42,65

Kumar et al. identified and synthesized derivatives of 1,3,4-oxadiazole based on pyridine.⁶⁶ An evaluation was conducted on various cancer cell lines, including HeLa, DU145, HepG2, and MBA-MB-231, representing cervical, prostate, liver, and breast cancers, respectively. Compounds 92 and 93 (Fig. 18), demonstrated the highest efficacy as anticancer agents, showing cytotoxicity at concentrations below 15 μM. The IC₅₀ values for the compounds against the specified cell lines were 9.8, 8.2, 9.5, and 8.7 μM for compound 92, and 12.8, 10.1, 11.6, and 9.9 μM for compound 93, respectively.⁶⁶ Rubino et al. reported Compound 94 (Fig. 18) and assessed it against several human cell lines, including MCF-7, HepG2 and HCT116. Compound 94 demonstrates the most potent antitumor effect by inducing cell death, with IC₅₀ values of 20.2, 4.0, and 1.1 μM, respectively, by utilizing the MTT method.⁶⁷ Sankhe et al. prepared and screened seven derivatives containing oxadiazole for their cytotoxic properties.⁶⁸ The study was conducted on the HepG2 and the MCF-7 cell lines. Among the seven drug candidates, compound 95 (Fig. 18) exhibited the highest proliferative inhibition activity, with an IC₅₀ value of 52.71 μM on HepG2.⁶⁸ Kumar et al. developed a collection of oxadiazole-based compounds using a convergent synthetic approach. The anticancer properties of these compounds were assessed through in vitro assays conducted on HeLa, Caco-2, HepG2, and MCF-7 cell lines. Compound 96 (Fig. 18) exhibited notable potency with an IC₅₀ of 8.6 μM, similar to the reference drug 5-fluorouracil 25 (Fig. 5) in the breast cancer cell line.⁶⁹ Adimule et al. examined the synthesis of analogs featuring oxadiazole and thiophene, which were then assessed for their anticancer efficacy against the Caco-2, PANC-1, and HepG2 cell lines, in comparison to the standard drug 5-fluorouracil 25 (Fig. 5). The results demonstrated that compound 97a (Fig. 18) displayed considerable cytotoxicity, closely aligning with the standard, against the Caco-2 cell line, with an IC₅₀ value of 5.3 μM. Compound 97b showed moderate cytotoxicity against HepG2 with IC₅₀ of 28.4 μM.⁷⁰

Bondock et al. developed a small library of analogs derived from the oxadiazole structure, which were assessed for anticancer activity through in vitro methods among them, compound 98 (Fig. 19), demonstrated the highest efficacy against multiple human tumor cell lines, including HepG2, VERO, and WI-38. The IC₅₀ values for this compound are 12.4 μM, 17.3 μM, and 15.8 μM, respectively.³⁹ Ren et al. conducted an evaluation of designed and synthesized derivatives of 1,3,4-oxadiazole-2-amino-podophyllotoxin as potential antitumor agents, utilizing the MTT assay.⁷¹ Compound 99 (Fig. 19), exhibited notable antiproliferative activity in the HepG2 cell line, evidenced by an IC₅₀ value of 1.29 μM. Compound 99 (Fig. 19) was found to inhibit the expression of the gene and protein for DNA topoisomerase IIb, causing S-phase arrest and ultimately resulting in apoptosis of tumor cells.⁷¹

Fig. 19 Compounds (98 and 99).

Compounds 100 and 101 (Fig. 20) exhibited relative cytotoxicity against HepG2 cells, with IC₅₀ values of 2.6 and 5.8 μM, respectively, in comparison to the reference drug 5-Fluorouracil 25 (Fig. 5).⁷²

Fig. 20 Compounds (100 and 101).

4 Conclusion

An overview of the research on possible medication candidates with various oxadiazole ring isomers that exhibit tolerable biological activity. Utilizing the nucleus is a crucial strategy in the development and synthesis of anticancer drugs since its presence has a clear direct impact on biological activity. The literature has demonstrated the use of oxadiazole as a scaffold for the synthesis of various agents, and various mechanisms have also been demonstrated to account for the various mechanisms of action that arise when this scaffold is used. Lastly, the use of oxadiazole derivatives is a very effective and promising strategy for the synthesis and design of upcoming anticancer drugs.

Abbreviations

A2780	human ovarian cancer cell line
A375	human melanoma cell line
A431	human epidermoid cancer cell line
A549	adenocarcinomic human alveolar basal epithelial cells
B16-F10	melanoma cell line
BGC823	human papillomavirus-related endocervical adenocarcinoma
Caco-2	human epithelial colorectal adenocarcinoma
CCK-8	cell counting kit-8
CDK2	cyclin dependant kinase 2
FDA	food and drug administration
GI50	growth inhibition 50%
HDAC8	histone deacetylase 8
HeLa	human epithelial cancer
HepG2	hepatoblastoma
HT-29	adherent epithelial cell line
IC50	half maximal inhibitory concentration
IMR32	human neuroblastoma cell line
LD50	lethal dose 50%
MCF-7	michigan cancer foundation-7
MDA-MB-231	M D anderson – metastatic breast – 231 human breast cancer cell line
MTT	colorimetric assay to measure cell survival
NCD	non communicable disease
QSAR	quantitative structure–activity relationship
SGC-7901	stomach cancer
SMMC-7721	human hepatocellular carcinoma
SW1116	colorectal cancer
SW1116	colorectal cancer
T47D	human ductal breast epithelial tumor

Conflicts of interest

The authors declare no conflict of interest.

Data availability

No data was used for the research described in this review article.

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