Microwave-assisted single-step synthesis of cyclic and acyclic β-aminosulfones and evaluation of their antifungal activity targeting CYP51

Abstract

The alarming rise of drug resistance has created an urgent need for novel antifungal agents. On the other hand, growing environmental concerns necessitate the development of sustainable alternatives to conventional synthetic methods for active pharmaceutical ingredients (APIs). β-Aminosulfones represent a potent yet underexplored functionality in biologically active compounds. In this work, a series of β-aminosulfone derivatives, designed as potential antifungal agents, were synthesized via a one-step, reagent-free, catalyst-free double aza-Michael addition of 2-aminobenzothiazoles, biogenic amines, or aromatic amines with different vinyl sulfones. The reactions were carried out in water under microwave irradiation (150 °C, 10 min), affording β-aminosulfones in excellent yields by simple filtration, without the need for further work-up or purification. This cost-effective process makes the production cost comparable to raw materials (e.g., compound 3d at $3.43 per g). Molecular docking, performed using the Glide module of the Schrödinger suite, revealed potential inhibitory activity against the fungal target CYP51 (PDB ID: 5V5Z), with reasonably good docking scores ranging from −5.69 to −8.25 kcal mol⁻¹ for benzothiazole derivatives and −5.73 to −7.05 kcal mol⁻¹ for biogenic amines. In silico ADMET profiling of selected compounds indicated promising drug-like attributes, satisfying Lipinski's rule. β-Aminosulfones were screened for their in vitro antifungal activity against various Candida species, and they exhibited MIC values ranging from 16 to 64 μg mL⁻¹. Notably, one compound (3d, 0.051 μM) showed comparable potency to fluconazole (0.052 μM) against Candida glabrata. Through ergosterol depletion assays, the mechanism of antifungal activity could be linked to the CYP51 inhibition pathway. Although these compounds exhibited moderate docking scores against 1KZN for antibacterial activity (−3.96 to −5.63 kcal mol⁻¹), the spot test revealed insignificant inhibition. Cytotoxicity studies with selected molecules revealed that these aza-sulfones are non-toxic to human cells, encouraging further studies with β-aminosulfone scaffolds.