Novel fluoroquinolones containing 2‐arylamino‐2‐oxoethyl fragment: Design, synthesis, evaluation of antibacterial and antituberculosis activities and molecular modeling studies

Abstract

Novel substituted fluoroquinolone derivatives, compounds 6-20 were designed, synthesized, and evaluated for antituberculosis and antibacterial activity. Antibacterial activities of the compounds were determined and compound 14 was found to be the most potent antimicrobial agent owing to minimal inhibitory concentration (MIC) value of <1.16 μg/μl for all tested bacteria. Further, compounds were tested in vitro for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv. Most of the compounds showed antimycobacterial effects with 1.56-25.00 μg/ml MIC values. Compounds 14 and 18 were found to be the most active derivatives due to their MIC at 1.56 μg/ml. Selected compounds 11, 14, 17, and 18 were tested for M. tuberculosis DNA supercoiling assay and they had IC 50 values within a range of 6.35-15 μM. Mechanism of binding to DNA gyrase enzymes was evaluated using in silico molecular modeling studies and it was shown that compounds 6-20 adopt a similar binding mode as already known for fluoroquinolone drugs.

Synthesis and Biological Evaluation of Diphenyl Ether‐Linked Quinolone Derivatives as Antibacterial Agents

“…The synthesis of the designed 1-cyclopropyl-6-fluoro-7-(4-(2-((4phenoxyphenyl)amino)-2-oxoethyl)piperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (7 a-w, 8 a-e, 9 a-m) is depicted in scheme 1. Various substituted phenols (2 a-w) were reacted with 4-fluoro nitrobenzenes in the presence of K 2 CO 3 in DMF to give the nitro diphenyl ether intermediate (3), which was then reduced to get the amine intermediate (5) in the presence of iron in ammonium chloride in ethanol and water (4 : 1). The amine intermediate was then reacted with chloroacetyl chloride/ chloropropanoyl chloride to yield the amide intermediate 5 which on reaction with ciprofloxacin/lomefloxacin in the presence of triethylamine and a catalytic amount of KI in DMF to give the titled derivatives in good yields.…”

“…DNA gyrase, a type II topoisomerase, resolves the topological problems during DNA replication. [3][4][5] Thus, targeting DNA gyrase could lead to developing new antibiotics with a lower probability of resistance. Fluoroquinolones (FQs) are known to be the most active synthetic antibacterial agents for treating several infectious diseases.…”

“…The lipophilic substitutions on the piperazine nitrogen are considered favourable for better bioavailability, safety, and efficacy of the designed compound. [3,[9][10][11] Diphenyl ethers like triclosan (V) and its derivatives are known to be potent antibacterial agents. [12][13][14] Developing new antibacterial agents by hybridizing two active scaffolds can lead to molecules having better inhibitory activities against the resistant bacteria.…”

“…In this prospect, Kulabas et al reported different aniline-linked ciprofloxacin as antibacterial and anti-mycobacterial agents, of which compound VI showed good inhibition against gram + ve and gram -ve bacteria with a MIC ranging from 1.25 to 4 μg/mL. [3] Noha et al reported ciprofloxacin-sulfonamide hybrids as potent antibacterial agents inhibiting the gram-positive and gramnegative bacteria with a MIC of 0.31-0.422 μM and potent dual inhibition of DNA Gyrase and topo IV with MIC of 0.43-1.1 μM of which compound VII (Figure 1) was found to be 4 fold more potent than the parent drug ciprofloxacin. [16] Hamada et al, reported N-4-piperazinyl thiadiazole and oxadiazole ciprofloxacin derivatives with compound VIII with good antibacterial activity against a panel of bacterial pathogens with MIC ranging from 1-1.31 μg/mL.…”

Drug re‐engineering and repurposing: A significant and rapid approach to tuberculosis drug discovery

“…Fluoroquinolone has been recognized as a "parental" subunit to develop molecules with high medicinal benefits and included as a "universal" treatment regimen under various medical evaluations, [114] which have facilitated many researchers to develop more fluoroquinolonebased molecules. [115,116] The presence of fluorine atoms in the structure has been well-known to boost the overall pharmacological activity of the compound. One such example is the most popular antibiotic drug ciprofloxacin which is widely used to treat several bactericidal infections.…”