Design, Synthesis of Some Innovative Indolo[3,2-c]Isoquinoline-5-One Analogs and Associated Bioactivities, Pharmacophore, Molecular Docking, MEP, and Conceptual DFT Studies

Abstract

A series of novel triazolothiadiazolethione and triazolothiadiazine appended indolo[3,2-c]isoquinoline-5-one were designed, synthesized, and validated by IR, 1H, 13C NMR, and mass spectroscopy strategies. All compounds are determined by their DFT investigations with B3LYP/def2-TZVP basis set level, ionization potentials, and electron affinities at vertical (IPv and EAv) and adiabatic parameters (IPA and EAA). Compound 3a has demonstrated the greatest values for these parameters. The compounds’ HOMO-LUMO (FMOs) and MEP maps were performed. The optimized structure of the compounds was estimated in global hardness, softness, global electrophilicity, and dipole moment. To find new drug candidates, different in vitro biological activities were implemented employing antimicrobial activity: Gram-negative bacteria were significantly suppressed by compound 4a, whereas gram-positive bacteria were strongly inhibited by compounds 3c and 3a has significant antifungal and anticancer effects. Compound 4b is profoundly antioxidant with IC50 value of 8.74 ± 1.93 µg/mL and MIC value of 0.25 µg/mL for antituberculosis properties. Thereafter, all of the compounds were subjected to e-pharmacophore approach to molecular docking studies. Compound 4a exhibited the best docking score (−8.458 kcal/mol) and docking interactions with active binding sites of 1TL8 receptor.