Novel 1,2,4-oxadiazole-chalcone/oxime hybrids as potential antibacterial DNA gyrase inhibitors: Design, synthesis, ADMET prediction and molecular docking study

Tarek S Ibrahim; Ahmad J Almalki; Amr H Moustafa; Rasha M Allam; Gamal El-Din A Abuo-Rahma; Hussein I El Subbagh; Mamdouh F A Mohamed

doi:10.1016/j.bioorg.2021.104885

Novel 1,2,4-oxadiazole-chalcone/oxime hybrids as potential antibacterial DNA gyrase inhibitors: Design, synthesis, ADMET prediction and molecular docking study

Bioorg Chem. 2021 Jun:111:104885. doi: 10.1016/j.bioorg.2021.104885. Epub 2021 Apr 1.

Authors

Tarek S Ibrahim¹, Ahmad J Almalki², Amr H Moustafa³, Rasha M Allam⁴, Gamal El-Din A Abuo-Rahma⁵, Hussein I El Subbagh⁶, Mamdouh F A Mohamed⁷

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Egypt. Electronic address: tmabrahem@kau.edu.sa.
² Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
³ Department of Chemistry, Faculty of Science, Sohag University, Sohag 82524, Egypt.
⁴ Pharmacology Department, National Research Centre, Cairo 12622 (ID: 60014618), Egypt.
⁵ Department of Medicinal Chemistry, Faculty of Pharmacy, Minia University, Minia 61519, Egypt; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Deraya University, New Minia, Minia, Egypt.
⁶ Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt.
⁷ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Sohag University, 82524 Sohag, Egypt. Electronic address: mamdouh.fawzi@pharm.sohag.edu.eg.

PMID: 33838559
DOI: 10.1016/j.bioorg.2021.104885

Abstract

New antibacterial drugs are urgently needed to tackle the rapid rise in multi-drug resistant bacteria. DNA gyrase is a validated target for the development of new antibacterial drugs. Thus, in the present investigation, a novel series of 1,2,4-oxadiazole-chalcone/oxime (6a-f) and (7a-f) were synthesized and characterized by IR, NMR (¹H and ¹³C) and elemental analyses. The title compounds were evaluated for their in-vitro antimicrobial activity by the modified agar diffusion method as well as their E. coli DNA gyrase inhibitory activity. The minimum inhibitory concentration (MIC) and the structure activity relationships (SARs) were evaluated. Among all, compounds 6a, 6c-e, 7b and 7e were the most potent and proved to possess broad spectrum activity against the tested Gram-positive and Gram-negative organisms. Additionally, compounds 6a (against S. aureus), 6c (against B. subtilis and E. hirae), 6e (against E. hirae), 6f, 7a and 7c (against E. coli) and 7d (against B. subtilis), with MIC value of 3.12 μM were two-fold more potent than the standard ciprofloxacin (MIC = 6.25 μM). Mechanistically, compounds 6c, 7c, 7e and 7b had good inhibitory activity against E. coli gyrase with IC₅₀ values of 17.05, 13.4, 16.9, and 19.6 µM, respectively, in comparison with novobiocin (IC₅₀ = 12.3 µM) and ciprofloxacin (IC₅₀ = 10.5 µM). The molecular docking results at DNA gyrase active site revealed that the most potent compounds 6c and 7c have binding mode and docking scores comparable to that of ciprofloxacin and novobiocin suggesting their antibacterial activity via inhibition of DNA gyrase. Finally, the predicted parameters of Lipinski's rule of five and ADMET analysis showed that 6c and 7c had good drug-likeness and acceptable physicochemical properties. Therefore, the hybridization of the chalcone and oxadiazole moieties could be promising lead as antibacterial candidate which merit further future structural optimizations.

Keywords: 1,2,4-Oxadiazole; ADMET; Antibacterial; Chalcone; DNA gyrase; Docking studies.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Bacillus subtilis / drug effects
DNA Gyrase / metabolism*
Dose-Response Relationship, Drug
Drug Design*
Enterococcus / drug effects
Escherichia coli / drug effects
Escherichia coli / enzymology
Microbial Sensitivity Tests
Molecular Docking Simulation*
Molecular Structure
Staphylococcus aureus / drug effects
Structure-Activity Relationship
Topoisomerase II Inhibitors / chemical synthesis
Topoisomerase II Inhibitors / chemistry
Topoisomerase II Inhibitors / pharmacology*

Substances

Anti-Bacterial Agents
Topoisomerase II Inhibitors
DNA Gyrase