In Silico Evaluation of Quinolone-Triazole and Conazole-Triazole Hybrids as Promising Antimicrobial and Anticancer Agents

Abstract

Cancer remains one of the leading causes of death globally, highlighting the urgent need for novel anticancer therapies with higher efficacy and reduced toxicity. Similarly, the rise in multidrug-resistant pathogens and emerging infectious diseases underscores the critical demand for new antimicrobial agents that target resistant infections through unique mechanisms. This study used computational approaches to investigate twenty quinolone-triazole and conazole-triazole hybrid derivatives as antimicrobial and anticancer agents (1-20) with nine reference drugs. By studying their interactions with 6 bacterial DNA gyrase and 10 cancer-inducing target proteins (E. faecalis, M. tuberculosis, S. aureus, E. coli, M. smegmatis, P. aeruginosa and EGFR, MPO, VEGFR, CDK6, MMP1, Bcl-2, LSD1, HDAC6, Aromatase, ALOX15) and comparing them with established drugs such as ampicillin, cefatrizine, fluconazole, gemcitabine, itraconazole, ribavirin, rufinamide, streptomycin, and tazobactam, compounds 15 and 16 emerged as noteworthy antimicrobial and anticancer agents, respectively. In molecular dynamics simulations, compounds 15 and 16 had the strongest binding at -10.6 kcal mol^-1 and -12.0 kcal mol^-1 with the crucial 5CDQ and 2Z3Y proteins, respectively, exceeded drug-likeness criteria, and displayed extraordinary stability within the enzyme's pocket over varied temperatures (300-320 K). In addition, we used density functional theory (DFT) to calculate dipole moments and molecular orbital characteristics and analyze the thermodynamic stability of putative antimicrobial and anticancer derivatives. This finding reveals a well-defined, possibly therapeutic relationship, supported by theoretical and future in vitro and in vivo studies. Compounds 15 and 16, thus, emerged as intriguing contenders in the fight against infectious diseases and cancer.

Keywords: anticancer; antimicrobial; conazole; quinolone; triazole.

Figure 1

Structures of the reference drugs.

Figure 2

Molecular docking configurations: (A) a compound positioned within the protein pocket; (B) active site visualization; (C) hydrogen bonding in the solid state (Purple = Hydrogen bond donor surface, Green = Hydrogen bond acceptor surface); (D) protein-ligand interaction displayed in a 2D diagram for (I) ligand 15 with modeled protein topoisomerase II (5CDQ) and (II) ligand 16 with modeled protein LSD1 (2Z3Y).

Figure 3

Plots depicting the count of intermolecular hydrogen bonds over time (ps) for hydrogen bond stabilization in (A) the protein complex of topoisomerase II and compounds 12, 14, 15, and reference drug fluconazole; and (B) the protein complex of LSD1 and compounds 13, 16, 17, and reference drug gemcitabine (Black = protein-compound complex, Red = protein-reference drug complex).

Figure 4

Principal component analysis (PCA) of MD trajectories at (A) 300 K, (B) 305 K, (C) 310 K, and (D) 320 K of (I) topoisomerase II-compound 15 complex and (II) LSD1-compound 16 complex (intermediate states are indicated by white dots, energetically unstable conformations are depicted by blue dots with scattering, and stable conformation states are represented by red dots).

Figure 5

Structures of quinolone–triazole and conazole–triazole hybrid derivatives (1–9).

Figure 6

Structures of quinolone–triazole and conazole–triazole hybrid derivatives (10–20).