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ABSTRACT: In view of the worldwide spread of multidrug resistance of Mycobacterium tuberculosis, there is an urgent need to discover antitubercular agents with novel structures. Thymidine monophosphate kinase from M. tuberculosis (TMPKmt) is an attractive target for antitubercular chemotherapy. We report here the identification of potent antitubercular compounds targeting TMPKmt using virtual screening methods. For this purpose we have developed a pharmacophore hypothesis based on the substrate and known TMPKmt inhibitors and employed it to screen the Maybridge small molecule database. The molecular docking was then performed in order to select the compounds on the basis of their ability to form favorable interactions with the TMPKmt active site. In addition, we applied straightforward weighting using structure interaction fingerprints to include additional knowledge into structure based virtual screening. Eight compounds were acquired and evaluated for antitubercular activity against M. tuberculosis H37Rv in vitro, and out of these 3 compounds showed MIC of 3.12 microg/mL whereas 2 compounds showed MIC of 12.5 microg/mL. All the active compounds were found to be nontoxic in Vero cell lines and mice bone marrow macrophages. All the identified hits highlighted a key hydrogen bonding interaction with Arg74. The observed pi-stacking interaction with Phe70 was also produced by the identified hits. These hits represent promising starting points for structural optimization in hit-to-lead development.
Journal of Chemical Information and Modeling 01/2009; 49(1):35-42. · 4.68 Impact Factor
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ABSTRACT: Frequency of tuberculosis and malaria is progressively increasing worldwide. New emerging strain of bacterium and resistance to currently available drugs make this field more conscientious and alarming. In this connection a series of substituted quinolinyl chalcones and substituted quinolinyl pyrimidines were synthesized and evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H(37)R(V) and antimalarial activity against NF-54 strain of Plasmodium falciparum. A comparison of structure-activity relationship reveals that different physicochemical and structural requirements exist for these two activities. Out of synthesized compounds, compound nos. 22 and 23 have shown antitubercular activity of MIC 3.12 microg/mL and were nontoxic against VERO, MBMDM cell lines and compounds 54, 55, and 56 have shown antimalarial activity of MIC 1 microg/mL.
European journal of medicinal chemistry 12/2008; 44(5):2081-91. · 3.27 Impact Factor
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ABSTRACT: An economical and facile synthesis of alpha,alpha'-(EE)-bis(benzylidene)-cycloalkanones was achieved by the reaction of cycloalkanones with different aromatic aldehydes using ethanolic KOH in good yields. Few of the selected compounds were reduced with NaBH(4) to the respective alpha,alpha'-(EE)-bis(benzylidene)-cycloalkanols. All these compounds and our earlier synthesized cyclohexyl phenyl methanols were evaluated for their antitubercular, antifungal and antibacterial activities. Several compounds displayed moderate antitubercular activity with MIC=12.5-1.56 microg/mL. However, none of the compounds displayed any significant antifungal activity.
European journal of medicinal chemistry 10/2008; 44(4):1705-9. · 3.27 Impact Factor
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ABSTRACT: A series of glycosyl thioacetamide and glycosyl sulfonyl acetamide derivatives have been prepared following a convenient reaction protocol and evaluated for their antitubercular activity against Mycobacterium tuberculosis H(37)Rv. Amongst 32 compounds evaluated 3 compounds were effective in inhibiting mycobacterial growth at MIC of 6.25 microg/mL, 6 compounds at MIC of 3.125 microg/mL and 1 compound at MIC of 1.56 microg/mL. All active compounds were found nontoxic in Vero cell lines and mice bone marrow macrophages.
Bioorganic & medicinal chemistry letters 08/2008; 18(14):4002-5. · 2.65 Impact Factor
