Synthesis of acetylenic 17α-ethynylestradiol derivatives as potential trypanocidal oral drugs: In vitro and in silico evaluation

The cross-coupling Sonogashira reaction of 17α-ethynylestradiol (EE2) with 4-iodobenzoic acid and 1-iodo-4-nitrobenzene to give two new derivatives 1 and 2, along with the 17α-(4-aminophenyl)ethynyl-estra-1,3,5(10)-triene-3,17β-diol 3 is reported. The compounds were characterized using 1D and 2D NMR techniques, FTIR in the solid state, mass spectrometry and elemental analysis. The correlation in the HMBC spectrum between the acetylenic carbon signal at 85.7 ppm and the aromatic protons at 7.50 ppm, and the presence of the IR bands at 3700–2300, 2217, and 1694 cm⁻¹, support clearly the formation of compound 1. Similarly, the correlation in the HMBC spectrum between the signals at 84.8 and 7.63 ppm, and the IR bands at 2218, 1518, 1339, 818 and 749 cm⁻¹ support the obtention of compound 2. According to the in silico absorption, distribution, metabolism, excretion (ADME) properties of EE2 derivatives, they could act as drugs for oral and topic administration, with gastrointestinal absorption, and good bioavailability. The trypanocidal activity of compounds 1, 2, and 3 was evaluated in vitro against the epimastigote stage of three T. cruzi strains, Ninoa, TH, and INC5, and their cytotoxicity over the J774.2 macrophage cell line was assayed. Derivative 1 showed higher trypanocidal activity than Benznidazole and Nifurtimox against epimastigotes of Ninoa strain, whereas the INC5 strain showed high sensitivity to EE2. None of the compounds showed antibacterial or antifungal activity. Nonetheless, compound 1 could represent an alternative to current trypanocidal drugs.