Synthesis of 5-enamine-4-thiazolidinone derivatives with trypanocidal and anticancer activity

Serhii Holota; Anna Kryshchyshyn; Halyna Derkach; Yaroslava Trufin; Inna Demchuk; Andrzej Gzella; Philippe Grellier; Roman Lesyk

doi:10.1016/j.bioorg.2019.01.045

Synthesis of 5-enamine-4-thiazolidinone derivatives with trypanocidal and anticancer activity

Bioorg Chem. 2019 May:86:126-136. doi: 10.1016/j.bioorg.2019.01.045. Epub 2019 Jan 22.

Authors

Serhii Holota¹, Anna Kryshchyshyn², Halyna Derkach³, Yaroslava Trufin², Inna Demchuk², Andrzej Gzella⁴, Philippe Grellier⁵, Roman Lesyk⁶

Affiliations

¹ Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, 69 Pekarska, Lviv 79010, Ukraine; Department of Organic Chemistry and Pharmacy, Lesya Ukrainka Eastern European National University, Volya Avenue 13, 43025 Lutsk, Ukraine.
² Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, 69 Pekarska, Lviv 79010, Ukraine.
³ Department of Chemistry, Ivano-Frankivsk National Medical University, 2 Halytska, Ivano-Frankivsk 76018, Ukraine.
⁴ Department of Organic Chemistry, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznan, Poland.
⁵ National Museum of Natural History, UMR 7245 CNRS-MNHN, Team APE, CP 52, 57 Rue Cuvier, Paris 75005, France.
⁶ Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, 69 Pekarska, Lviv 79010, Ukraine; Department of Public Health, Dietetics and Lifestyle Disorders, Faculty of Medicine, University of Information Technology and Management in Rzeszow, Sucharskiego 2, 35-225 Rzeszow, Poland. Electronic address: dr_r_lesyk@org.lviv.net.

PMID: 30690336
DOI: 10.1016/j.bioorg.2019.01.045

Abstract

A series of novel 2-(5-aminomethylene-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropionic acid ethyl esters has been synthesized. Target compounds were evaluated for their trypanocidal activity towards Trypanosoma brucei brucei and Trypanosoma brucei gambiense. Several hit-compounds (8, 10, 12) inhibited growth of the parasites at sub-micromolar concentrations (IC₅₀ 0.027-1.936 µM) and showed significant selectivity indices (SI = 108-1396.2) being non-toxic towards the human primary fibroblasts. The screening of anticancer activity in vitro within NCI DTP protocol allowed to identify active 2-(5-{[5-(2,4-dichlorobenzyl)-thiazol-2-ylamino]-methylene}-4-oxo-2-thioxothiazolidin-3-yl)-3-phenylpropionic acid ethyl ester 14 that demonstrated inhibition against all 59 human tumor cell lines with the average GI₅₀ value of 2.57 μM. It was established that the activity type (antitrypanosomal or anticancer) as well as its level depends on the character of enamine fragment in the C5 position of thiazolidinone core.

Keywords: 5-ene-4-thiazolidinones; Anticancer activity; Antitrypanosomal activity; X-ray.

MeSH terms

Animals
Antiprotozoal Agents / chemical synthesis
Antiprotozoal Agents / chemistry
Antiprotozoal Agents / pharmacology*
Cell Line
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Humans
Molecular Structure
Parasitic Sensitivity Tests
Rats
Structure-Activity Relationship
Thiazolidines / chemical synthesis
Thiazolidines / chemistry
Thiazolidines / pharmacology*
Trypanocidal Agents / chemical synthesis
Trypanocidal Agents / chemistry
Trypanocidal Agents / pharmacology*
Trypanosoma brucei brucei / drug effects*

Substances

Antiprotozoal Agents
Thiazolidines
Trypanocidal Agents