Journal
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Volume 102, Issue -, Pages 320-333Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2015.07.047
Keywords
Antimalarial; Drug lead; Indole; Reagent-based diversity
Categories
Funding
- Fundacao para a Ciencia e Tecnologia (FCT) [PTDC/SAU-FAR/114864/2009, PEst-OE/SAU/UI4013/2014, SFRH/BD/80162/2011]
- Fundação para a Ciência e a Tecnologia [PTDC/SAU-FAR/114864/2009, SFRH/BD/80162/2011] Funding Source: FCT
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A series of 3-piperidin-4-yl-1H-indoles with building block diversity was synthesized based on a hit derived from an HTS whole-cell screen against Plasmodium falciparum. Thirty-eight compounds were obtained following a three-step synthetic approach and evaluated for anti-parasitic activity. The SAR shows that 3-piperidin-4-yl-1H-indole is intolerant to most N-piperidinyl modifications. Nevertheless, we were able to identify a new compound (10d) with lead-like properties (MW = 305; cLogP = 2.42), showing antimalarial activity against drug-resistant and sensitive strains (EC50 values similar to 3 mu M), selectivity for malaria parasite and no cross-resistance with chloroquine, thus representing a potential new chemotype for further optimization towards novel and affordable antimalarial drugs. (C) 2015 Elsevier Masson SAS. All rights reserved.
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