Design, synthesis, explorations of DFT, PM6, molecular docking with SAR-CoV-2 Mpro and anticancer properties of novel indolo[2,3-c]isoquinoline analogues

Abstract

A novel series of indolo[2,3-c]isoquinoline derivatives, coupled with pyrazole and pyrazolo[3,4-d]pyrimidinone rings bearing substituted Cl, OCH3, CH3, and H groups II, II(a-d), were successfully synthesized, exhibiting significant biological and pharmacological relevance. Computational chemistry using the semiempirical method PM6 via MOPAC software was employed to investigate their thermochemical properties. Compound IIIb displayed a lower heat formation (ΔHf) value of 68.89873 kcal/mole, indicating enhanced stability, whereas compound IId exhibited a higher ΔHf value of 151.32004 kcal/mole, suggesting lesser stability. Density functional theory (DFT) at B3LYP/def2-TZVP def2/J was utilized for analyzing electronic structures and geometric optimization. The HOMO-LUMO energy gap (ΔEg) followed an ascending order in the pyrimidinone>pyrazole series, with IIIb possessing the lowest energy gap (ΔEg = 2.994 eV) and IIc having the highest (ΔEg = 3.433 eV). Compound IIa displayed the highest electrophilicity index (χ = 3.540 eV) and exhibited potent anti-cancer activity, as observed in derivatives II and III(a-d). Additionally, compounds IIa, IIb, and IIc demonstrated promising interactions with amino acids of the SARS-CoV-2 main protease (PDB:7e18).