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

Abstract

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.

Keywords: ADMET studies; DFT studies; Hep-G2 cancer cell line; SAR; anticancer; hemolysis; in silico profiling; indole–triazole; thrombolysis.

Figure 1

Representative commercially available drugs containing indole and 1,2,4-triazole moieties.

Figure 2

Rationale design of synthesized indole–1,2,4-triazole hybrids as anti-Hep-G2 agents.

Scheme 1

Synthetic pathway for the preparation of indole–1,2,4-triazole-based–S–alkylated N–aryl acetamide derivatives 8a–f.

Figure 3

Anti-HepG-2 cytotoxic potential of indole–triazoles 8a–f.

Figure 4

Structure–activity relationship of the most bioactive indole–1,2,4-triazole compounds as anti-Hep-G2 pharmacophore.

Figure 5

Two-dimensional (lower panel) and three-dimensional (upper panel) interactive conformations of AKT1 enzyme with compound 8b.

Figure 6

Two-dimensional conformational and interactive images of AKT1+8b (upper panel) and AKT1+8f (lower panel).

Figure 7

Molecular dynamics simulation analysis. The docked complexes were investigated for structure stability using carbon alpha-based RMSD (top) and RMSF (bottom).

Figure 8

MEP distribution map of 8a, 8b, and 8f.

Figure 9

Molecular orbitals of 8a, 8b, and 8f (HOMO in the right and LUMO in the left side).

Figure 9

Molecular orbitals of 8a, 8b, and 8f (HOMO in the right and LUMO in the left side).