Synthesis of 5-enamine-4-thiazolidinone derivatives with trypanocidal and anticancer activity
Serhii Holota1, Anna Kryshchyshyn2, Halyna Derkach3
1Department 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.
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.
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