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

doi:10.1016/j.ejmech.2015.07.047

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

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

Authors

Sofia A Santos¹, Amanda K Lukens², Lis Coelho³, Fátima Nogueira³, Dyann F Wirth², Ralph Mazitschek⁴, Rui Moreira⁵, Alexandra Paulo⁶

Affiliations

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.

PMID: 26295174
DOI: 10.1016/j.ejmech.2015.07.047

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antimalarials / chemical synthesis
Antimalarials / chemistry*
Antimalarials / pharmacology*
Antimalarials / therapeutic use
Cell Survival / drug effects
Dose-Response Relationship, Drug
Hep G2 Cells
Humans
Indoles / chemical synthesis
Indoles / chemistry
Indoles / pharmacology*
Malaria / drug therapy*
Malaria / parasitology
Molecular Structure
Niacinamide / analogs & derivatives*
Niacinamide / chemical synthesis
Niacinamide / chemistry
Niacinamide / pharmacology
Parasitic Sensitivity Tests
Plasmodium falciparum / drug effects*
Plasmodium falciparum / growth & development
Structure-Activity Relationship

Substances

(4-(1H-indol-3-yl)piperidin-1-yl)(pyridin-3-yl)methanone
Antimalarials
Indoles
Niacinamide