Liquid Phase Combinatorial Synthesis of Novel Benzimidazole as Antitubercular Agents

Abstract

Tuberculosis (TB) is one of the world's deadliest infectious diseases, caused by Mycobacterium tuberculosis (Mtb). Additionally, an upsurge has been observed in recent times in development of resistance to existing therapies and hence the treatments of several TB strains have led to failure causing deaths in multiple developing and under developed nations. In this present work, various extensive literature reviews have been carried out to assess the existing database established by multiple research groups and following that an establishment of the thorough implementation and assessment of all possible computational approaches have been done. Firstly, the QSAR studies were established on the basis of compounds reported in the literature using two techniques viz. pharmacophore based modelling and docking based modelling. Finally the best model was selected for further designing on the basis of the results obtained and the designed molecules were docked on the selected FTsZ protein crystal structure in-silico and the molecules with good score and excellent binding interactions were synthesized as the first and second series of molecules by using liquid phase combinatorial synthesis and they were confirmed by various analytical approaches such as Mass, IR, 1H-NMR, 13C-NMR and HPLC. However, the results of the biological assessment were not encouraging as the compounds demonstrated poor biological activity. Compound 146 was the only molecule out of the twenty two synthesized to be with the biological activity at 50 µM. Thus, further series of molecules, were developed on the basis of the first results and with the correlation of the new molecules with the QSAR, docking studies and the biological activity results from the first series and the SAR observed from the compound 146. Leading to the designing of 50 new molecules from which fifteen from series 3 and ten from series four were synthesized via implementation of liquid phase synthesis and the isolated molecules were confirmed by analytical approaches such as Mass, IR, 1H-NMR, 13C-NMR and HPLC. Moreover, single crystal XRD analysis was performed for 162 and have been reported to crystal data bank. Among these, compound 192 exhibited the best in vitro antitubercular activity against Mtb H37Rv in liquid cultures. Compound 192 was also found to be non-cytotoxic in macrophage assay. Finally, in addition to compound 192 other compounds 166, 167, 196, 197 and 199 also exhibited anti-mycobacterial activity in THP-1 macrophages. Moreover, all the active compounds were subjected to in silico cLogP evaluation and ADMET profiling studies and results demonstrated that the compounds would exhibit good absorption and distribution profiles along with lower levels of toxicity. Furthermore, the present study was also expanded by the screening of the first and second series of compounds by carrying out various computational analysis and finding a new target which could be a probable hit for the molecules and the results were encouraging against hDHODH enzyme and actual enzyme assays confirmed the in-silico establishments; Biological assay results indicated that the inhibition of hDHODH enzyme which is over expressed in cancer was achieved with good results for compounds 122, 123, 137, 142 and 143.