Synthesis, Cytotoxic, and Computational Screening of Some Novel Indole-1,2,4-Triazole-Based S -Alkylated N -Aryl Acetamides.

Molecular hybridization has emerged as the prime and most significant approach for the development of novel anticancer chemotherapeutic agents for combating cancer. In this pursuit, a novel series of indole-1,2,4-triazol-based N -phenyl acetamide structural motifs 8a - f were synthesized and screened against the in vitro hepatocellular cancer Hep-G2 cell line. The MTT assay was applied to determine the anti-proliferative potential of novel indole-triazole compounds 8a - f , which displayed cytotoxicity potential as cell viabilities at 100 µg/mL concentration, by using ellipticine and doxorubicin as standard reference drugs. The remarkable prominent bioactive structural hybrids 8a , 8c, and 8f demonstrated good-to-excellent anti-Hep-G2 cancer chemotherapeutic potential, with a cell viability of (11.72 ± 0.53), (18.92 ± 1.48), and (12.93 ± 0.55), respectively. The excellent cytotoxicity efficacy against the liver cancer cell line Hep-G2 was displayed by the 3,4-dichloro moiety containing indole-triazole scaffold 8b, which had the lowest cell viability (10.99 ± 0.59) compared with the standard drug ellipticine (cell viability = 11.5 ± 0.55) but displayed comparable potency in comparison with the standard drug doxorubicin (cell viability = 10.8 ± 0.41). The structure-activity relationship (SAR) of indole-triazoles 8a - f revealed that the 3,4-dichlorophenyl-based indole-triazole structural hybrid 8b displayed excellent anti-Hep-G2 cancer chemotherapeutic efficacy. The in silico approaches such as molecular docking scores, molecular dynamic simulation stability data, DFT, ADMET studies, and in vitro pharmacological profile clearly indicated that indole-triazole scaffold 8b could be the lead anti-Hep-G2 liver cancer therapeutic agent and a promising anti-Hep-G2 drug candidate for further clinical evaluations.