Design and development of novel Mycobacterium tuberculosis L-alanine dehydrogenase inhibitors

Abstract

In the present study, we used crystal structure of MTB L-AlaDH protein complex with N6-methyl adenosine for structure based virtual screening of in house database to identify new small molecule inhibitors for MTB-L-AlaDH. Two molecules identified as better leads and were modified synthetically to obtain thirty novel analogues belonging to 2-iminothiazolidine-4-ones and 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamides. Among the screened compounds four (4n, 4o, 12 and 14) emerged as potent inhibitors displaying IC50 values ranging from 0.58 ± 0.02 to 1.74 ± 0.03 μM against MTB-L-AlaDH and were non-cytotoxic at 50 μM. Some of these synthesized compounds also exhibited good activity against nutrient starved dormant MTB cells. The most potent inhibitors were found to stabilize the protein which was confirmed biophysically through differential scanning fluorimetry.

Keywords: 2-Iminothiazolidine-4-ones; 4,5,6,7-tetrahydrothieno[2,3-c]pyridine-3-carboxamides; Dormant tuberculosis; Tuberculosis; l-Alanine dehydrogenase.