Design and Synthesis of Menthol and Thymol Derived Ciprofloxacin: Influence of Structural Modifications on the Antibacterial Activity and Anticancer Properties

Abstract

Sixteen new Ciprofloxacin derivatives were designed and successfully synthesized. In an in silico experiment, lipophilicity was established for obtained compounds. All compounds were screened for antimicrobial activity using standard and clinical strains. As for Gram-positive hospital microorganisms, all tested derivatives were active. Measured MICs were in the range 1–16 µg/mL, confirming high antimicrobial potency. Derivative 12 demonstrated activity against all standard Gram-positive Staphylococci, within the range of 0.8–1.6 µg/mL and was confirmed as the leading structure with MICs 1 µg/mL for S. pasteuri KR 4358 and S. aureus T 5591 (clinical strains). All compounds were screened for their in vitro cytotoxic properties via the MTT method. Three of the examined compounds (3, 11 and 16) showed good activity against cancer cells, and in parallel were found not to be cytotoxic toward normal cells. Doxorubicin SI ranged 0.14–1.11 while the mentioned three ranged 1.9–3.4. Selected Ciprofloxacin derivatives were docked into the crystal structure of topoisomerase II (DNA gyrase) in complex with DNA (PDB ID: 5BTC). In summary, leading structures were established (3, 11, 12 and 16). We have observed poor results in preformed studies for disubstituted derivatives, suggesting that 3-oxo-4-carboxylic acid core is the active DNA-gyrase binding site, and when structural changes were made in this fragment, there was an observed decrease in antibacterial potency.

Menthol- and thymol-based ciprofloxacin derivatives against Mycobacterium tuberculosis: in vitro activity, lipophilicity, and computational studies

“…Nevertheless, it's worth noting that multiple interactions with bacterial cells contribute to their antimicrobial activity. In previous 10 and current studies, menthol and thymol moieties were chosen for several interactions with bacterial cells, such as: damage to membrane proteins, reduced ATP synthesis, increased membrane permeability and membrane fluidity causing leakage of ions, a decrease in the pH gradient across the cytoplasmic membrane 11 , 12 .…”

“…For this study, we have picked Ciprofloxacin over Gatifloxacin as starting material, although both possess accessible piperazinyl moiety. Our previous examination indicated that thymol and menthol Ciprofloxacin derivatives showed promising antibacterial activities and low toxicity to eukaryotic cells 10 . Encouraged by the results, we have decided to continue our study.…”

“…What should be underlined, is that all derivatives were not cytotoxic in MTT assay. As an example, the selectivity index (3.4) was determined for compound 6 , with IC 50 29.5 ± 2.1 µM against human colon cancer cells (HCT-116) and with no cytotoxic effect on human immortal keratinocyte cell line from adult human skin (HaCaT) 10 .…”

“… a Results from our earlier work 10 for comparison. b Point mutations in the A subunit (Gyr A) included: D89G, S90V, S91P, and D94A.…”

“…Considering that fluoroquinolones (FQs) antibiotics are promising starting structures in the anti-TB drug discovery pipeline, our team has decided to continue the broad study of Ciprofloxacin derivatives and investigate the anti-TB properties of previously synthesized menthol and thymol hybrids 10 . Biological assays covered reference strain of M. tuberculosis (H37Rv) and also clinical isolates; Linezolid susceptible SIR 168/22 and Linezolid resistant SIRE 22/22 collected from patients of the National Tuberculosis and Lung Diseases Research Institute.…”