Design, synthesis and molecular docking study of thienopyrimidin-4(3H)-thiones as antifungal agents

In an attempt to find a new class of antimicrobial agents, a series of thienopyrimidin-4(3 H )-thiones 4 ( H1–H36 ) were synthesized and evaluated for in vitro antifungal activity against Candida albicans (NCIM 3471), Aspergillus niger (NCIM 545), and Penicillium chrysogenum (NCIM 709). The title compounds were synthesized by thionation of thienopyrimidin-4(3 H )-ones 3 ( H1–H36 ) using Lawesson’s reagent. All the compounds were characterized using elemental analytical (C, H, and N) and spectral (FT-IR, 1 H NMR, 13 C NMR and MS) data. Among the tested compounds, 5-(4-chlorophenyl)-2-(pyridin-3-yl)thieno[2,3-d]pyrimidine-4(3 H )-thione 4 ( H11 ), 2-sulfanyl-5,6,7,8-tetrahydro[1]benzothieno[2,3- d ]pyrimidine-4(3 H )-thione 4 ( H18 ), and 2-(butylsulfanyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidine-4(3 H )-thione 4 ( H32 ) were identified as potentially excellent antifungal agents. They exhibited potent antifungal activity against C. albicans (MIC; 4 μg/mL), A. niger (MIC; 2 μg/mL), and P. chrysogenum (MIC; 2 μg/mL) comparable with that of ketoconazole. The binding mode of compounds by SP docking studies shows that it fits well into the active site cavity of DHFR. Lipinski’s rule and in silico ADME pharmacokinetic parameters are within the acceptable range defined for human use thereby indicating their potential as drug-like molecules.