Synthesis And Structure-activity Relationships Of Nitazoxanide Derivatives

Nitazoxanide is thiazoles benzamides with a broad-spectrum anti-infective activity, notableefficacy against anaerobic bacteria, worms and protozoa, and has a significant therapeutic effect onparasite infection.This study was carried out to synthesize a series of derivatives of nitazoxanide.Through in vitro efficacy evaluation, some active derivatives with inhibiting Clostridium difficilewere screened. Then the relationships between their structure and antibacterial activity were studiedand summarized.1. We synthesized a total of27compounds including two kindes of nitazoxanide derivatives(thiazole and pyrimidine) by amide reaction. All compounds were characterized by1HNMR,13CNMR,MS,24products of which have not been reported.2. Agar dilution method was used and Clostridium difficile was selected as teste bacterial. Theresults showed that MICs of seven compounds were less than or equal to4μg/mL, in which fourcompounds is synthesized for the first time. Five compounds with5-nitrothiazole Skeleton have goodinhibitory effect and their MIC were less than or equal to1μg/mL. MIC ofN-(5-nitrothiazol-2-yl)-4-(trifluoromethyl)benzamide (1e) is lower than that of NTZ, indicating that1e is better than NTZ for the in vitro inhibition activity of Clostridium difficile. The experimentsshowed that the nitro in5position of the thiazole ring and the pyrimidine ring is essential group toproduce its biological activity, which are consistent with report before.3.2D and3D quantitative structure activity relationships of28nitazoxanide derivatives werestudied with DS-QSAR software. A simple2D-QSAR equation was obtained by genetic functionapproximation.pMIC=0.75552+4.9471*X1+1.397*X2+1.7507*X3-1.8442*X4n=23r2=0.9052r2(adj)=0.8842r2(pred)=0.8402The results showed that the activity of nitazoxanide derivatives to inhibit Clostridium difficile waspositively correlated with molecule connectivity index, molecule local charge surface parameter, andwas negatively correlated with molecule connectivity index molecule flexibility index. It was found thatthe adjacent, meta position of the benzene ring and5position of the heterocyclic substituent were themain factors of the compound activity through the equipotential diagram in the model through3D-QSAR (r2=0.967, q2=0.744).This study provided theoretical guidance for further design ofstructural diversification of nitazoxanide derivatives.