Synthesis, E-pharmacophore, Molecular Docking Studies with SARS-CoV-2 Protease, Their Biological Properties and DFT Calculation of Some New Indolo[3,2-c]Isoquinoiline Hybrids

Abstract

A series of novel indolo[3,2-c]isoquinoline hybrids derivatives were synthesized. On the basis of spectroscopic and analytical data, the structures of newly synthesized compounds were determined. They were further evaluated for their in vitro antimicrobial, antioxidant anticancer and anti-TB activities. Results reveal that compounds 4a and 5a displayed better potency against all bacterial strains and compound 3b showed significant antifungal action against all fungi tested. Compound 4b display excellent antioxidant capability. Compounds 3a, 4a, and 5a bearing chloro on indolo[3,2-c]isoquinoline ring were found have higher potency against all cancer cell lines. Compound 5b displayed potent antitubercular activity against Mycobacterium tuberculosis H37Rv strain with MIC 0.12 μg/mL. Consequently, a five-point e-pharmacophore model (AADDR) was built. Docking studies displayed that compounds 2a, 2b, 3a, 4b, and 4c exhibited stronger interactions and higher binding affinity toward Glu166, Gln189, and His41, which are critical amino acid residues that play a significant role in PDB: 7D1M (SARS-CoV-2 Mpro) through hydrogen bonding, hydrophobic and π-π interactions. Further, frontier molecular orbitals studies were executed to understand their orbital energies and HOMO-LUMO lowest energy gap is 8.39 eV shown by compound 5a.