title: Accepting the Invitation to Open Innovation in Malaria Drug Discovery: Synthesis, Biological Evaluation, and Investigation on the Structure-Activity Relationships of Benzo[b]thiophene-2-carboxamides as Antimalarial Agents.
abstract: Malaria eradication is a global health priority, but current therapies are not always suitable for providing a radical cure. Artemisinin has paved the way for the current malaria treatment, the so-called Artemisinin-based Combination Therapy (ACT). However, with the detection of resistance to ACT, innovative compounds active against multiple parasite species and at multiple life stages are needed. GlaxoSmithKline has recently disclosed the results of a phenotypic screening of an internal library, publishing a collection of 400 antimalarial chemotypes, termed the "Malaria Box". After analysis of the data set, we have carried out a medicinal chemistry campaign in order to define the structure-activity relationships for one of the released compounds, which embodies a benzothiophene-2-carboxamide core. Thirty-five compounds were prepared, and a description of the structural features responsible for the in vitro activity against different strains of P. falciparum, the toxicity, and the metabolic stability is herein reported.
authors.forename: Marco
authors.identifier: 0000-0001-9190-3712
authors.initials: M
authors.lastname: Pieroni
authors.forename: Elisa
authors.initials: E
authors.lastname: Azzali
authors.affiliation: Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università di Milano , via Pascal 36, Milano 20133, Italy.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Basilico
authors.affiliation: Dipartimento di Scienze Farmacologiche e Biomolecolari, Università di Milano , via Pascal 36, Milano 20133, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Parapini
authors.affiliation: Department of Biochemistry and Molecular Biophysics, Kansas State University , Manhattan, Kansas 66506, United States.
authors.forename: Michal
authors.initials: M
authors.lastname: Zolkiewski
authors.forename: Claudia
authors.initials: C
authors.lastname: Beato
authors.forename: Giannamaria
authors.initials: G
authors.lastname: Annunziato
authors.forename: Agostino
authors.initials: A
authors.lastname: Bruno
authors.forename: Federica
authors.initials: F
authors.lastname: Vacondio
authors.affiliation: Centro Interdipartimentale Misure (CIM) 'G. Casnati', University of Parma , Parco Area delle Scienze 23/A, 43124 Parma, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Costantino
mesh_terms: D000577:Amides / Q000737:chemistry; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006801:Humans; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000577:Amides; D000962:Antimalarials; D013876:Thiophenes; C026163:benzo(b)thiophene-2-carboxylic acid