Novel indolo [3,2-c]isoquinoline-5-one-6-yl [1,2,4]triazolo [3,4-b] [1,3,4]thiadiazole analogues: Design, synthesis, anticancer activity, docking with SARS-CoV-2 Omicron protease and MESP/TD-DFT approaches

Highlights

• Synthesis of indolo [2,3-c]isoquinoline derivatives containing different substitutions (Cl,CH₃,H, NH₂,NO₂).

• Structural conformation of the unknown compounds with the help of their TLC, spectral studies viz, IR, ¹H,¹³C NMR, mass spectroscopy and elemental analysis (HRMS) etc.

• Syntheiszed compounds were evaluated for their anticancer activity against various different human cancer cell lines, like (Breast Carcinoma), (Lung carcinoma) and (Cervical carcinoma) etc.

• Molecular docking study of synthesized compounds against SARS-CoV-2 omicron protease approaches.

• Molecular electrostatic potential (MESP) analysis.

• Time-Dependent density functional theory (TDDFT) and frontier molecular orbitals studies .

Abstract

Indoloisoquinoline derivatives are associated with varieties of biological and pharmacological properties. Therefore, we herein reported the synthesis of novel series of indolo [3,2-c]isoquinoline incorporated with [1,2,4]triazolo [3,4-b] [1,3,4]thiadiazole moieties. Spectroscopic methods were used to determine the chemical structures of these molecules. Whereas, the B3LYP functional with the def2-SVP basis set were used to improve TD-DFT geometries and solvent effects. Investigations, which are directly connected to the optical spectra (absorption and emission) of molecules. These findings reveals that the compound 3d-f with a strong electron acceptor NO₂ exhibited UV−visible spectra peaks to near infrared (NIR) range in solvents. Compound 3e exhibited a lowest ∆E of 2.28 eV in MeCN. Further, among the newly synthesized compounds 3d and 3g exhibits highest activity against four cell lines with strongest potent cytotoxicity, as contrasted to the control drug (Doxorubicin). Docking experiments revealed that compounds in contrast to 3a and 3d had strong interactions with Asn₃₂₂, Met₃₂₃, Ala₃₈₇,Ala_386, Gln₅₀₆ and Gly₃₂₆ with a greater binding affinity which are important amino acid residues that play a key role in SARS-CoV-2 Omicron main protease (M^pro) through hydrophobic, hydrogen bonding, Pi-sigma, Pi-sulfur and van der Waals interactions.