Exploring the 3-piperidin-4-yl-1H-indole scaffold as a novel antimalarial chemotype.

Eur J Med Chem

Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Professor Gama Pinto, 1640-003 Lisbon, Portugal. Electronic address:

Published: September 2015

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 ∼ 3 μM), 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.

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http://dx.doi.org/10.1016/j.ejmech.2015.07.047DOI Listing

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