title: Design, synthesis and antimalarial evaluation of novel thiazole derivatives.
abstract: As part of our medicinal chemistry program's ongoing search for compounds with antimalarial activity, we prepared a series of thiazole analogs and conducted a SAR study analyzing their in vitro activities against the chloroquine-sensitive Plasmodium falciparum 3D7 strain. The results indicate that modifications of the N-aryl amide group linked to the thiazole ring are the most significant in terms of in vitro antimalarial activity, leading to compounds with high antimalarial potency and low cytotoxicity in HepG2 cell lines. Furthermore, the observed SAR implies that non-bulky, electron-withdrawing groups are preferred at ortho position on the phenyl ring, whereas small atoms such as H or F are preferred at para position. Finally, replacement of the phenyl ring by a pyridine affords a compound with similar potency, but with potentially better physicochemical properties which could constitute a new line of research for further studies.
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: José María
authors.initials: JM
authors.lastname: Bueno
authors.affiliation: Departamento de Química Inorgánica y Orgánica, Univ. Jaume I, 12071 Castellón, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Carda
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Benigno
authors.initials: B
authors.lastname: Crespo
authors.affiliation: Departamento de Química Orgánica, Facultad de Química, Univ. de València, Calle Dr. Moliner 50, 46100 Burjassot, Spain. Electronic address: ana.cunat@uv.es.
authors.forename: Ana Carmen
authors.initials: AC
authors.lastname: Cuñat
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: de Cozar
authors.affiliation: Tres Cantos Medicines Development Campus, DDW, GlaxoSmithKline, Severo Ochoa 2, 28760 Tres Cantos, Spain. Electronic address: maria-luisa.d.leon@gsk.com.
authors.forename: María Luisa
authors.initials: ML
authors.lastname: León
authors.affiliation: Departamento de Química Orgánica, Facultad de Química, Univ. de València, Calle Dr. Moliner 50, 46100 Burjassot, Spain.
authors.forename: J Alberto
authors.initials: JA
authors.lastname: Marco
authors.affiliation: Departamento de Química Orgánica, Facultad de Química, Univ. de València, Calle Dr. Moliner 50, 46100 Burjassot, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Roda
authors.affiliation: Departamento de Química Orgánica, Facultad de Química, Univ. de València, Calle Dr. Moliner 50, 46100 Burjassot, Spain.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Sanz-Cervera
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D056945:Hep G2 Cells; D006801:Humans; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity
chemical_list: D000962:Antimalarials; D013844:Thiazoles
keywords: Antimalarials; Malaria; Structure–activity relationship; Synthesis; Thiazoles