Pyrazole-Thiazole Core-Containing Analogs Exhibit Adjunctive Activity with Meropenem against Carbapenem-Resistant Enterobacteriaceae (CRE)

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 mu M) values. Of this series of molecules, four compounds displayed notable adjunctive potential, with FIC and MAC values of 0.25 and 32 mu M, 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.

Automated summary

A total of 20 novel derivatives of compound KP-40 containing Pyrazole-thiazole core were designed and synthesized through traditional SAR analysis. Four of the compounds showed significant adjunctive potential with improved solubility, and key physicochemical properties for the development of active Gram-negative antibacterials were revealed through further analysis using PEMPO algorithm. Consideration of PEMPO scores prior to synthesis of analogs may be a simple yet effective strategy in conjunction with traditional SAR approaches for designing potent Gram-negative antibacterials.