Komal Kalani, Sarfraz Alam, Vineeta Chaturvedi, Feroz Khan and Santosh Kumar Srivastava*
As a part of our drug discovery program for anti-tubercular agents, dihydroartemisinin (DHA-1) was screened against Mtb H37Rv, which showed moderate anti-tubercular activity (>25 .0 μg/mL). These results prompted us to carry out chemical transformation of DHA-1 into various derivatives and study their antitubercular potential. Thus, DHA-1was semi-synthetically converted into four new acyl derivatives (DHA-1A – DHA-1D) and in-vitro evaluated for their anti-tubercular potential against Mycobacterium tuberculosis H37Rv virulent strain. The derivatives, DHA-1C (12-O-(4-nitro) benzoyl; MIC 12.5 µg/mL) and DHA-1D (12-O-chloro acetyl; MIC 3.12µg/mL) showed significant activity against the pathogen. Further, in silico studies of the most active derivative (DHA-1D) showed interaction with ARG448 and inhibiting the mycobacterium enzymes. Additionally, it showed no cytotoxicity towards the Vero C1008 cells and Mouse bone marrow derived macrophages. Finally, DHA-1D also killed 62% intracellular M. tuberculosis in Mouse bone marrow macrophage infection model. To the best of our knowledge this is the first ever report on the antitubercular potential of dihydroartemisinin and its derivatives. Since, dihydroartemisinin is widely used as an antimalarial drug; these results may be of great help in anti-tubercular drug development from a very common, inexpensive, and non toxic natural product.
Dihydroartemisinin, semi-synthetic derivatives, anti-tubercular activity, in-silico studies
Medicinal Chemistry Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, Metabolic & Structural Biology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, Microbiology Division, Central Drug Research Institute, Lucknow-226001, Metabolic & Structural Biology Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, Medicinal Chemistry Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow