Format

Send to

Choose Destination
Eur J Med Chem. 2015 Sep 18;102:320-33. doi: 10.1016/j.ejmech.2015.07.047. Epub 2015 Jul 31.

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

Author information

1
Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Professor Gama Pinto, 1640-003 Lisbon, Portugal; Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
2
The Broad Institute, Infectious Diseases Initiative, Cambridge, MA 02142, USA; Harvard School of Public Health, Department of Immunology and Infectious Disease, Boston, MA 02115, USA.
3
UEI Malaria, Centro da Malária e Doenças Tropicais, IHMT, Universidade Nova de Lisboa, Rua da Junqueira, 100, P-1349-008 Lisboa, Portugal.
4
Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA; The Broad Institute, Infectious Diseases Initiative, Cambridge, MA 02142, USA; Harvard School of Public Health, Department of Immunology and Infectious Disease, Boston, MA 02115, USA.
5
Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Professor Gama Pinto, 1640-003 Lisbon, Portugal.
6
Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Professor Gama Pinto, 1640-003 Lisbon, Portugal. Electronic address: mapaulo@ff.ulisboa.pt.

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.

KEYWORDS:

Antimalarial; Drug lead; Indole; Reagent-based diversity

PMID:
26295174
DOI:
10.1016/j.ejmech.2015.07.047
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center