title: Synthesis of pyrazoline-thiazolidinone hybrids with trypanocidal activity.
abstract: A series of novel 4-thiazolidinone-pyrazoline conjugates have been synthesized and tested for anti-Trypanosoma brucei activity. Screening data allowed us to identify five thiazolidinone-pyrazoline hybrids, which possess promising trypanocidal activity, with IC50 ≤ 1.2 μM. The highest active thiazolidinone-pyrazoline conjugates 3c and 6b (IC50 values of 0.6 μM and 0.7 μM, respectively) were 6-times more potent antitrypanosomal agents than nifurtimox. In addition, these compounds, as well as 6d and 6e had selectivity index higher than 50, and were more selective than nifurtimox. SAR study included substituent variations at the pyrazoline moiety, modifications of N3 position of the thiazolidinone portion, elongation of the linker between the heterocycles, as well as rhodanine-isorhodanine isomerism. It was also shown that methyl or aryl substitution at the thiazolidinone N3-position is crucial for trypanocidal activity.
authors.affiliation: Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, Lviv 79010, Ukraine.
authors.forename: Dmytro
authors.initials: D
authors.lastname: Havrylyuk
authors.affiliation: Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, Lviv 79010, Ukraine.
authors.forename: Borys
authors.initials: B
authors.lastname: Zimenkovsky
authors.affiliation: Enamine Ltd., Alexandra Matrosova 23, Kyiv 01103, Ukraine.
authors.forename: Olexandr
authors.initials: O
authors.lastname: Karpenko
authors.affiliation: National Museum of Natural History, UMR 7245 CNRS-MNHN, Team BAMEE, CP 52, 57 Rue Cuvier, 75005 Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Grellier
authors.affiliation: Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, Pekarska 69, Lviv 79010, Ukraine. Electronic address: dr_r_lesyk@org.lviv.net.
authors.forename: Roman
authors.initials: R
authors.lastname: Lesyk
mesh_terms: D000818:Animals; D002460:Cell Line; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D011720:Pyrazoles / Q000737:chemistry*; D051381:Rats; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014344:Trypanocidal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D014346:Trypanosoma brucei brucei / Q000187:drug effects
chemical_list: D011720:Pyrazoles; D053778:Thiazolidines; D014344:Trypanocidal Agents; C031280:pyrazole
keywords: 4-Thiazolidinones; Antitrypanosomal activity; Pyrazolines; Synthesis