Design, Synthesis, and Antibacterial Screening of Some Novel Heteroaryl-Based Ciprofloxacin Derivatives as DNA Gyrase and Topoisomerase IV Inhibitors

Lamya H Al-Wahaibi; Amer A Amer; Adel A Marzouk; Hesham A M Gomaa; Bahaa G M Youssif; Antar A Abdelhamid

doi:10.3390/ph14050399

Design, Synthesis, and Antibacterial Screening of Some Novel Heteroaryl-Based Ciprofloxacin Derivatives as DNA Gyrase and Topoisomerase IV Inhibitors

Pharmaceuticals (Basel). 2021 Apr 22;14(5):399. doi: 10.3390/ph14050399.

Authors

Lamya H Al-Wahaibi¹, Amer A Amer², Adel A Marzouk³, Hesham A M Gomaa⁴, Bahaa G M Youssif⁵, Antar A Abdelhamid^{2

6}

Affiliations

¹ Department of Chemistry, College of Sciences, Princess Nourah bint Abdulrahman University, Riyadh P.O. Box 84428, Saudi Arabia.
² Department of Chemistry, Faculty of Science, Sohag University, Sohag 82524, Egypt.
³ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt.
⁴ Pharmacology Department, College of Pharmacy, Jouf University, Aljouf 72341, Saudi Arabia.
⁵ Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
⁶ Chemistry Department, Faculty of Science, Albaha University, Albaha P.O. Box 1988, Saudi Arabia.

Abstract

A novel series of ciprofloxacin hybrids comprising various heterocycle derivatives has been synthesized and structurally elucidated using ¹H NMR, ¹³C NMR, and elementary analyses. Using ciprofloxacin as a reference, compounds 1-21 were screened in vitro against Gram-positive bacterial strains such as Staphylococcus aureus and Bacillus subtilis and Gram-negative strains such as Escherichia coli and Pseudomonas aeruginosa. As a result, many of the compounds examined had antibacterial activity equivalent to ciprofloxacin against test bacteria. Compounds 2-6, oxadiazole derivatives, were found to have antibacterial activity that was 88 to 120% that of ciprofloxacin against Gram-positive and Gram-negative bacteria. The findings showed that none of the compounds tested had antifungal activity against Aspergillus flavus, but did have poor activity against Candida albicans, ranging from 23% to 33% of fluconazole, with compound 3 being the most active (33% of fluconazole). The most potent compounds, 3, 4, 5, and 6, displayed an IC₅₀ of 86, 42, 92, and 180 nM against E. coli DNA gyrase, respectively (novobiocin, IC₅₀ = 170 nM). Compounds 4, 5, and 6 showed IC₅₀ values (1.47, 6.80, and 8.92 µM, respectively) against E. coli topo IV in comparison to novobiocin (IC₅₀ = 11 µM).

Keywords: antibacterial; ciprofloxacin; gyrase; heteroaryl; topoisomerase IV.

Grants and funding

Fast-track Research funding program/Princess Nourah Bint Abdulrahman University