Background: The most urgent clinical need is to discover potent agents capable of reducing the time of M-XDR tuberculosis therapy with a success rate comparable to susceptible tuberculosis. The last decade has seen the discovery of promising new agent classes for the management of tuberculosis, several of which are currently in clinical trials. However, given the high attrition rate during clinical development and emergence of resistance, the discovery of additional clinical candidates is clearly needed. Our drug discovery was accelerated by applying our unique assay system which is more relevant with in vivo condition. We reported on a promising novel class of thienothiazolocarboxamide (TTCA) compounds as potential leads that block Mycobacterium tuberculosis growth. In this study, we synthesized TTCA derivatives by structural modification. Through lead optimization, they showed good activity against TB replicating not only in the liquid broth culture medium but also within macrophage. Material/methods: In order to search for the novel scaffold which can be developed as potential antitubercular agents, about 30,270 compounds were subjected for phenotypic high-throughput screening (HTS) against not only to bacteria directly (extracellular) but also to infected bacteria inside the macrophages (intracellular). Compounds were subjected to screening in each HTS, and finally compounds which were active in both assays were selected. Once the hit was selected, synthesis was carried out in order to develop lead compounds supported by ADME/PK analyses of derivatives. Results: In this study, we synthesized TTCA derivatives by structural modification. We designed and aynthesized around 360 derivatives of TTCA. We have successfully synthesized two lead candidates with different R groups. TTCA compounds have better potency against intracellular bacteria. Also, TTCA compounds were active against tested clinical MDR strains with MIC less than 1uM. In vitro ADME and physicochemical properties profiling suggested that TTCA series have drug-like properties. In addition, TTCA series displayed not only potent in vivo efficacy but also orally available good in vivo pharmacokinetic(PK) properties.

Discovery of novel anti-tubercular agent for the treatment of MDR/XDR TB

2019 Spring National Meeting

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