Synthesis and antiprotozoal activity of 1,2,3,4-tetrahydro-2-thioxopyrimidine analogs of combretastatin A-4
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Eighteen 1,2,3,4-tetrahydro-2-thioxopyrimidine analogs (5a–j, 6a–e, and 7a–c) of combretastatin A-4 were synthesized with the objective of discovering compounds capable of controlling the growth of Trypanosoma lewisii, Leishmania tarantole, Plasmodium falciparum, and Giardia lamblia. Even though the target compounds demonstrated differential cytotoxicity against mammalian cancer cells, with IC50 values ranging from 0.5 to >100 μM, the range of activity against Trypanosoma, Leishmania, and Plasmodium, and to a good extent for Giardia, was narrow. The IC50 values of “active” compounds against the parasites ranged from about 10 μΜ to slightly greater than 50 μM. Specifically, compounds 5a, 5g, 5h, 6c, 7a, and 7c were not cytotoxic against mammalian cancer cells (IC50 > 100 μM) but showed good activity against the parasites, except Giardia (e.g., compounds 6c and 7a), suggesting that these compounds may act in a similar mechanism in parasites. Compounds 5f and 6b were previously shown to promote microtubule depolymerization in mammalian cells.
KeywordsCombretastatin Microtubule Cytotoxicity Antiparasite Trypanosoma Leishmania Plasmodium Giardia
The authors are grateful for the support received from the Howard Hughes Medical Institute, Conjura Pharmaceuticals, LLC, and Hope College.
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