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.
authors: 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.
authors: Sofia A
authors: SA
authors: Santos
authors: 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.
authors: Amanda K
authors: AK
authors: Lukens
authors: UEI Malaria, Centro da Malária e Doenças Tropicais, IHMT, Universidade Nova de Lisboa, Rua da Junqueira, 100, P-1349-008 Lisboa, Portugal.
authors: Lis
authors: L
authors: Coelho
authors: UEI Malaria, Centro da Malária e Doenças Tropicais, IHMT, Universidade Nova de Lisboa, Rua da Junqueira, 100, P-1349-008 Lisboa, Portugal.
authors: Fátima
authors: F
authors: Nogueira
authors: 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.
authors: Dyann F
authors: DF
authors: Wirth
authors: 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.
authors: Ralph
authors: R
authors: Mazitschek
authors: Research Institute for Medicines (iMed.ULisboa), Faculdade de Farmácia, Universidade de Lisboa, Av. Professor Gama Pinto, 1640-003 Lisbon, Portugal.
authors: Rui
authors: R
authors: Moreira
authors: 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.
authors: Alexandra
authors: A
authors: Paulo
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D015394:Molecular Structure; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development; D013329:Structure-Activity Relationship
chemical_list: C000608201:(4-(1H-indol-3-yl)piperidin-1-yl)(pyridin-3-yl)methanone; D000962:Antimalarials; D007211:Indoles; D009536:Niacinamide
keywords: Antimalarial; Drug lead; Indole; Reagent-based diversity