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Published on: February 9, 2021
In Silico Evaluation of Quinolone-Triazole and Conazole-Triazole Hybrids as Promising Antimicrobial and Anticancer
Humaera Noor Suha1, Mansour H Almatarneh2, Raymond A Poirier3
1Department of Biochemistry and Microbiology, North South University, Dhaka 1229, Bangladesh.
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.
Insights
Novel quinolone-triazole and conazole-triazole hybrids show promise as antimicrobial and anticancer agents. Compounds 15 and 16 demonstrated significant binding affinity and stability against bacterial and cancer targets, warranting further investigation.
Area of Science:
- Medicinal Chemistry
- Computational Drug Discovery
- Antimicrobial and Anticancer Research
Background:
- Global health challenges include rising cancer mortality and increasing antimicrobial resistance.
- There is a critical need for novel therapeutic agents with improved efficacy and reduced toxicity.
- Hybrid molecules offer a promising strategy for developing new drugs against resistant pathogens and cancer.
Purpose of the Study:
- To computationally investigate twenty quinolone-triazole and conazole-triazole hybrid derivatives (compounds 1-20) as potential antimicrobial and anticancer agents.
- To assess the binding interactions of these compounds with key bacterial and cancer-related protein targets.
- To evaluate the drug-likeness, stability, and electronic properties of promising hybrid derivatives.
Main Methods:
- In silico screening and molecular docking against bacterial DNA gyrase and ten cancer-related proteins.
- Molecular dynamics simulations to assess binding stability and enzyme interactions at varied temperatures.
- Density Functional Theory (DFT) calculations for electronic properties and thermodynamic stability analysis.
Main Results:
- Compounds 15 and 16 exhibited potent predicted activity as antimicrobial and anticancer agents, respectively.
- Compound 15 showed strong binding (-10.6 kcal mol⁻¹) to bacterial DNA gyrase (5CDQ), while compound 16 bound strongly (-12.0 kcal mol⁻¹) to a cancer target (2Z3Y).
- Both compounds demonstrated excellent stability in molecular dynamics simulations and met drug-likeness criteria.
Conclusions:
- Compounds 15 and 16 are identified as promising lead candidates for developing new antimicrobial and anticancer drugs.
- The study provides a theoretical foundation for further in vitro and in vivo validation of these hybrid derivatives.
- This research highlights the potential of hybrid molecular scaffolds in addressing urgent global health threats from infectious diseases and cancer.
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