TY - JOUR
T1 - Unexpected rearrangement of ivermectin in the synthesis of new derivatives with trypanocidal and antiplasmodial activities
AU - Sulik, Michał
AU - Fontinha, Diana
AU - Steverding, Dietmar
AU - Szymon, Sobczak
AU - Antoszczak, Michał
AU - Prudêncio, Miguel
AU - Huczyński, Adam
PY - 2024/1/5
Y1 - 2024/1/5
N2 - Ivermectin is a sixteen-membered macrolactone “wonder drug” of Nobel prize-honored distinction that exhibits a wide range of antiparasitic activities. It has been used for almost four decades in the treatment of various parasitic diseases in humans and animals. In this paper, we describe the synthesis of the first-in-class ivermectin derivatives obtained via derivatization of the C13 position, along with the unexpected rearrangement of the oxahydrindene (hexahydrobenzofuran) unit of the macrolide ring. The structural investigation of the rearrangement has been performed using the single-crystal X-ray diffraction method. The antiparasitic and cytotoxic activities of the newly synthesized derivatives were determined in vitro with the bloodstream form of Trypanosoma brucei brucei, the hepatic stage of Plasmodium berghei, and human leukemia HL-60 cells. The compounds with the highest trypanocidal activity were the C13-epi-2-chloroacetamide analogs of native (6h) or rearranged (7h) ivermectin. Both 6h and 7h displayed trypanocidal activities within a similar mid-nanomolar concentration range as the commercially used trypanocides suramin and ethidium bromide. Furthermore, 6h and 7h exhibited a comparable cytotoxic to trypanocidal ratio as the reference drug ethidium bromide. The double-modified compound 7a (C13-epi-acetamide of rearranged ivermectin) exhibited the highest activity against P. berghei grown in human hepatoma cells, which was 2.5 times higher than that of ivermectin. The findings of this study suggest that C13-epi-amide derivatives of ivermectin are suitable leads in the rational development of new antiparasitic agents.
AB - Ivermectin is a sixteen-membered macrolactone “wonder drug” of Nobel prize-honored distinction that exhibits a wide range of antiparasitic activities. It has been used for almost four decades in the treatment of various parasitic diseases in humans and animals. In this paper, we describe the synthesis of the first-in-class ivermectin derivatives obtained via derivatization of the C13 position, along with the unexpected rearrangement of the oxahydrindene (hexahydrobenzofuran) unit of the macrolide ring. The structural investigation of the rearrangement has been performed using the single-crystal X-ray diffraction method. The antiparasitic and cytotoxic activities of the newly synthesized derivatives were determined in vitro with the bloodstream form of Trypanosoma brucei brucei, the hepatic stage of Plasmodium berghei, and human leukemia HL-60 cells. The compounds with the highest trypanocidal activity were the C13-epi-2-chloroacetamide analogs of native (6h) or rearranged (7h) ivermectin. Both 6h and 7h displayed trypanocidal activities within a similar mid-nanomolar concentration range as the commercially used trypanocides suramin and ethidium bromide. Furthermore, 6h and 7h exhibited a comparable cytotoxic to trypanocidal ratio as the reference drug ethidium bromide. The double-modified compound 7a (C13-epi-acetamide of rearranged ivermectin) exhibited the highest activity against P. berghei grown in human hepatoma cells, which was 2.5 times higher than that of ivermectin. The findings of this study suggest that C13-epi-amide derivatives of ivermectin are suitable leads in the rational development of new antiparasitic agents.
U2 - 10.1016/j.ejmech.2023.115951
DO - 10.1016/j.ejmech.2023.115951
M3 - Article
VL - 263
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
M1 - 115951
ER -