Synthesis, crystallography, biological activity, and molecular modeling studies of some 3-Aryl-2-(4-(substitutedphenyl)thiazol-2-yl)acrylonitrile derivatives

• A series of 3-aryl-2-(4-(substitutedphenyl)thiazol-2-yl)acrylonitrilederivatives 1–16 were synthesized. • Crystal structure and packing of 10 were resolved via quantum crystallography, DFT was applied to predict solvated structure. • Target compounds were evaluated for in vitro antibacterial, antifungal, and antimycobacterial activity. • Trifluoromethyl derivative 10 showed promising antifungal activity. • Homology modelling and docking were performed to predict molecular mechanism of action. In this study, a series of 3-aryl-2-(4-(substitutedphenyl)thiazol-2-yl)acrylonitrile derivatives, was synthesized and their structures were elucidated using 1 H/ 13C NMR , IR, HRMS and quantum crystallography methods. Ab initio quantum mechanics (QM) was applied to predict their molecular geometry and frontier molecular orbital parameters (FMO) in aqueous medium. Molecular descriptors were calculated to predict their druglikeness. Antimicrobial activities of the synthesized compounds were investigated against Mycobacterium tuberculosis H37Rv strain, various Gram-positive and Gram-negative bacteria, and three Candida spp. were evaluated in vitro using isoniazid, ethambutol, ciprofloxacin, and fluconazole (Diflucan) as reference drugs. Among the tested compounds, 2-(4-(2,4-dichlorophenyl)thiazol-2-yl)-3-(4-(trifluoromethyl)phenyl)acrylonitrile ( 10 ) was found to be a promising antifungal agent with a minimum inhibitory concertation (MIC) value of 32 µg/mL against C. parapsilosis. Molecular docking was performed to explain the molecular mechanism of its activity. Based on these findings, the title compounds serve a promising starting point for further structure-activity relationships and medicinal chemistry studies.