3D-QSAR modeling and synthesis of new fusidic acid derivatives as antiplasmodial agents
Kaur, G Pavadai, E Wittlin, S Chibale, K
Kaur, G
Pavadai, E
Wittlin, S
Chibale, K
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Abstract
Wide spread Plasmodium falciparum ( P. falciparum) resistance has compromised existing antimalarial therapies to varying degrees. Novel agents, able to circumvent antimalarial drug resistance, are therefore needed. Fusidic acid is a unique antibiotic with a unique mode of action, which has shown weak in vitro antiplasmodial activity. Toward identifying new fusidic acid derivatives with superior antiplasmodial activity, a 3D-QSAR model was developed based on the antiplasmodial activity of previously synthesized fusidic acid derivatives. The validated Hypo 2 model was used as the 3D-structural search query to screen a fusidic acid-based combinatorial library. On the basis of the predicted activity and pharmacophore fit value, eight virtual hit compounds were selected and synthesized, including C-21 amide and C-3 ether derivatives. All synthesized hit compounds showed superior antiplasmodial activity compared to fusidic acid. Two C-21 amide derivatives displayed significant activity against the drug-sensitive NF54 strain with IC values of 0.3 μM and 0.7 μM, respectively. These two derivatives also displayed activity against the multidrug-resistant K1 strain, with an IC value of 0.2 μM and were found to be relatively noncytotoxic.
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2018-07-24
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ACS Publications
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Kaur G, Pavadai E, Wittlin S, Chibale K. 3D-QSAR Modeling and Synthesis of New Fusidic Acid Derivatives as Antiplasmodial Agents. J Chem Inf Model. 2018 Aug 27;58(8):1553-1560. doi: 10.1021/acs.jcim.8b00105.