New N -phenyl-4,5-dibromopyrrolamides and N -Phenylindolamides as ATPase inhibitors of DNA gyrase

Synthesis and Evaluation of N‐Phenylpyrrolamides as DNA Gyrase B Inhibitors

“…Based on the relatively high activity of one of our previously reported inhibitors with only a short COCH 3 substituent at the para position of the central aminobenzene ring [i.e., N‐ (4‐acetylphenyl)‐4,5‐dibromo‐1 H ‐pyrrole‐2‐carboxamide, IC 50 =1.6 μ m ], we decided to further explore the chemical space around this molecule by preparing a small library of its analogues (type III compounds, Figure ). Analogues were prepared with carboxylic groups attached directly to the central phenyl ring (X=OH, Y=H, Figure ), along with compounds with an additional hydroxy group on the phenyl ring (X=OH, Y=OH, Figure ), and compounds with an acetophenone functionality (X=CH 3 , Y=H, Figure ).…”

“…In a comparison of the activities of compounds with carboxylic acid groups with their hydrazide analogues, the former were generally more active. For example, carboxylic acid 7 (IC 50 =0.28 μ m ) displayed greater activity than its hydrazide analogue 9 (IC 50 =0.43 μ m ), compound A (IC 50 =0.45 μ m , reported previously) was more active than the corresponding hydrazide 8 (IC 50 =2.4 μ m ), and the carboxylic acid 19 b (IC 50 =0.16 μ m ) was more potent than the hydrazide 20 (IC 50 =1.6 μ m ). These differences are, most probably, due to the loss of ionic interactions with Arg136 in the case of hydrazide groups.…”

“…Seven of these compounds contained a free carboxylic acid group, which thus appears crucial for the activity. A possible reason for the weaker activities of compounds against S. aureus gyrase is that the adenine‐binding pocket of this enzyme is slightly smaller than that of E. coli gyrase, which would indicate that smaller groups are more effective in binding to the hydrophobic binding site, as discussed recently . In line with this, the two most active compounds against S. aureus gyrase, 19 e (IC 50 =4.1 μ m ) and 19 f (IC 50 =2.3 μ m ), contain smaller 3,4‐dichloro‐5‐methylpyrrole moieties, whereas the activities of their 4,5‐dibromopyrrolamide analogues 19 a (IC 50 =17 μ m ) and 19 b (IC 50 =22 μ m ) were slightly lower.…”

Design, synthesis, and biological evaluation of 1‐ethyl‐3‐(thiazol‐2‐yl)urea derivatives as Escherichia coli DNA gyrase inhibitors

“…We have recently designed and optimized several structural classes of pyrrolamide‐based DNA gyrase and topoisomerase IV inhibitors, which were based on the 4,5,6,7‐tetrahydrobenzo[1,2‐ d ]‐thiazole‐2,6‐diamine, benzo[1,2‐ d ]thiazole‐2,6‐diamine, 4‐aminopiperidine, and aniline scaffolds. In all of them, the 4,5‐dibromopyrrolamide moiety was shown to be an important structural feature, as it is necessary to achieve potent Escherichia coli DNA gyrase inhibition.…”

Design and Synthesis of Diverse Pyrrole‐2‐carboxamide Derivatives as a Potent Antibacterial Agents

“…The structural and therapeutic diversity coupled with the commercial viability of different types of small molecules has fascinated organic and medicinal chemists. The pyrrole‐2‐carboxamide moiety is a pharmacophores found as a core skeleton in molecules with diverse biological activities such as insecticidal , antibiofilm , antibacterial , ATPase inhibitors of DNA gyrase , DNA binding, topoisomerase I inhibition , inducible nitric oxide synthase (nNOS and iNOS) inhibitors , antifungal , anticancer , JAK2 inhibitors , CB2 receptor antagonists , and antitumor . Compounds with the pyrrole‐2‐carboxamide scaffold in their skeleton display better broad spectrum of biological activity shown in Figure .…”