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

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

Research output: Contribution to journal › Article › peer-review

30 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 language	English
Article number	8031
Pages (from-to)	320-333
Number of pages	14
Journal	European Journal of Medicinal Chemistry
Volume	102
DOIs	https://doi.org/10.1016/j.ejmech.2015.07.047
Publication status	Published - 18 Sept 2015

Keywords

Antimalarial
Drug lead
Indole
Reagent-based diversity

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ejmech.2015.07.047

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

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.",

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AU - Santos, Sofia A.

AU - Lukens, Amanda K.

AU - Coelho, Lis

AU - Nogueira, Fátima

AU - Wirth, Dyann F.

AU - Mazitschek, Ralph

AU - Moreira, Rui

AU - Paulo, Alexandra

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PY - 2015/9/18

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AB - 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.

KW - Antimalarial

KW - Drug lead

KW - Indole

KW - Reagent-based diversity

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JF - European Journal of Medicinal Chemistry

M1 - 8031

ER -

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

Abstract

Keywords

UN SDGs

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