Design and synthesis of ciprofloxacin-sulfonamide hybrids to manipulate ciprofloxacin pharmacological qualities: Potency and side effects

Noha M Ibrahim; Samar H Fahim; Mariam Hassan; Awatef E Farag; Hanan H Georgey

doi:10.1016/j.ejmech.2021.114021

Design and synthesis of ciprofloxacin-sulfonamide hybrids to manipulate ciprofloxacin pharmacological qualities: Potency and side effects

Eur J Med Chem. 2022 Jan 15:228:114021. doi: 10.1016/j.ejmech.2021.114021. Epub 2021 Nov 30.

Authors

Noha M Ibrahim¹, Samar H Fahim², Mariam Hassan³, Awatef E Farag¹, Hanan H Georgey⁴

Affiliations

¹ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, El-Kasr El-Eini Street, Cairo, 11562, Egypt.
² Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, El-Kasr El-Eini Street, Cairo, 11562, Egypt. Electronic address: samer.mohamed@pharma.cu.edu.eg.
³ Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, El-Kasr El-Eini Street, Cairo, 11562, Egypt.
⁴ Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, El-Kasr El-Eini Street, Cairo, 11562, Egypt; Pharmaceutical Chemistry Department, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo, 11786, Egypt.

PMID: 34871841
DOI: 10.1016/j.ejmech.2021.114021

Abstract

Fluoroquinolones are a class of antibacterial agents used clinically to treat a wide array of bacterial infections. Although being potent, susceptibility to CNS side effects limits their use. It was observed that improvements in absorption, activity and side effects were achieved via modifications at the N atom of the C7 of the side chain. To meet the increasing demand for development of new antibacterial agents, nineteen novel ciprofloxacin-sulfonamide hybrid molecules were designed, synthesized and characterized by IR, ¹H NMR and ¹³C NMR as potential antibacterial agents with dual DNA gyrase/topoisomerase IV inhibitory activity. Most of the synthesized compounds showed significant antibacterial activity that was revealed by testing their inhibitory activity against DNA gyrase, DNA topoisomerase IV as well as their minimum inhibitory concentration against Staphylococcus aureus. Six ciprofloxacin-sulfonamide hybrids (3f, 5d, 7a, 7d, 7e and 9b) showed potent inhibitory activity against DNA topoisomerase IV, compared to ciprofloxacin (IC50: 0.55 μM), with IC50 range: 0.23-0.44 μM. DNA gyrase was also efficiently inhibited by five ciprofloxacin-sulfonamide hybrids (3f, 5d, 5e, 7a and 7d) with IC50 range: 0.43-1.1 μM (IC50 of ciprofloxacin: 0.83 μM). Compounds 3a and 3b showed a marked improvement in the antibacterial activity over ciprofloxacin against both Gram-positive and Gram-negative pathogens, namely, Staphylococcus aureus Newman and Escherichia coli ATCC8739, with MIC = 0.324 and 0.422 μM, respectively, that is 4.2-fold and 3.2-fold lower than ciprofloxacin (MIC = 1.359 μM) against the Gram-positive Staphylococcus aureus, and MIC = 0.025 and 0.013 μM, respectively, that is 10.2-fold and 19.6-fold lower than ciprofloxacin (MIC = 0.255 μM) against the Gram-negative Escherichia coli ATCC8739. Also, the most active compounds showed lower CNS and convulsive side effects compared to ciprofloxacin with a concomitant decrease in GABA expression.

Keywords: Antibacterial activity; Ciprofloxacin; Convulsive effect; DNA gyrase; Fluoroquinolones; GABA expression; Sulfonamides; Topoisomerase IV.

MeSH terms

Animals
Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Ciprofloxacin / chemistry
Ciprofloxacin / pharmacology*
DNA Topoisomerase IV / antagonists & inhibitors*
DNA Topoisomerase IV / metabolism
Dose-Response Relationship, Drug
Drug Design*
Gram-Negative Bacteria / drug effects
Gram-Positive Bacteria / drug effects
Male
Mice
Microbial Sensitivity Tests
Molecular Docking Simulation
Molecular Structure
Structure-Activity Relationship
Sulfanilamide / chemistry
Sulfanilamide / pharmacology*
Topoisomerase Inhibitors / chemical synthesis
Topoisomerase Inhibitors / chemistry
Topoisomerase Inhibitors / pharmacology*

Substances

Anti-Bacterial Agents
Topoisomerase Inhibitors
Sulfanilamide
Ciprofloxacin
DNA Topoisomerase IV