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

Sofia A. Santos, Amanda K. Lukens, Lis Coelho, Fátima Nogueira, Dyann F. Wirth, Ralph Mazitschek, Rui Moreira, Alexandra Paulo

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number8031
Pages (from-to)320-333
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume102
DOIs
Publication statusPublished - 18 Sep 2015

Keywords

  • Antimalarial
  • Drug lead
  • Indole
  • Reagent-based diversity

UN Sustainable Development Goals (SDGs)

  • SDG 3 - Good Health and Well-Being

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