SYNTHESIS AND EVALUATION OF ANTITUBERCULOSIS ACTIVITY OF 1-ADAMANTYL HYDRAZIDE HYDRAZONES SUPPORTED WITH MOLECULAR DOCKING

Abstract

Tuberculosis is a significant cause of illness and death worldwide. More importantly, the multidrug resistance cases are increasing. This requires a strong need to develop novel compounds possessing antimycobacterial properties and to enhance current therapies. In view of this, novel 1-adamantyl derivatives were designed, synthesized and tested for its antituberculosis effectiveness against a susceptible strain of Mycobacterium tuberculosis (H37Rv). The samples were assessed using a classic growth based method, which involved the L.J. MIC method (Lowenstein and Jensen method). The results indicated that the synthesized 1-adamantyl hydrazide hydrazones (5-BVAC & 5-NVAC) showed significant antituberculosis activity when compared with known antituberculosis drug Isoniazid with minimum inhibitory concentration MIC of 0.9 ppm and 1.25 ppm.

The mode of interaction was studied by carrying molecular docking study with MmpL3 from M. smegmatis which has the similar genus as Mycobacterium tuberculosis (H37Rv) with similarity in cell structure and genetic organisation. The binding affinity score of best binding conformation of 5-BVAC & 5-NVAC was −8.7 Kcal/mol

The results show that 5-BVAC & 5-NVAC to be a new inhibitor of MmpL3 with the binding mode similar to that of other antituberculars that target MmpL3.  Hence the new scaffolds containing an adamantane and hydrazide hydrazone moiety may emerge as the potential anti TB agent, which can have the capability to enhance TB treatment in combination with other standard therapies.