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Pyrazole‐Thiazole Core‐Containing Analogs Exhibit Adjunctive Activity with Meropenem against Carbapenem‐Resistant Enterobacteriaceae (CRE)
Author(s) -
Kim Chungsik,
Kassu Mintesinot,
Smith Kenneth P.,
Kirby James E.,
Manetsch Roman
Publication year - 2021
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202100321
Subject(s) - thiazole , meropenem , carbapenem , pyrazole , chemistry , combinatorial chemistry , gram , rational design , efflux , gram negative bacteria , solubility , antibiotics , stereochemistry , bacteria , organic chemistry , biochemistry , antibiotic resistance , biology , escherichia coli , materials science , nanotechnology , gene , genetics
Pyrazole‐thiazole core‐containing compound KP‐40 and 20 novel derivatives were designed and synthesized through traditional SAR analysis. These molecules displayed adjunctive activity with meropenem against Gram‐negative bacteria evidenced by a range of fractional inhibitory concentration (FIC=0.5–0.25) and minimum adjunctive concentration (MAC=128–32 μM) values. Of this series of molecules, four compounds displayed notable adjunctive potential, with FIC and MAC values of 0.25 and 32 μM, respectively. Moreover, the solubility of these compounds was improved to an acceptable range. Further analysis using our “in house” permeation and efflux multi parameter optimization (PEMPO) algorithm revealed key physicochemical properties that may be critical for the development of active Gram‐negative antibacterials. Taking PEMPO scores into consideration prior to executing synthesis of analogs may be a simple, yet rapid and effective strategy that can be used in conjunction with traditional SAR approaches to aid in the design of potent Gram‐negative antibacterials.