Design, synthesis, and antitumor activity of coumarin, isoxazole, pyrazole, pyridine, and pyrimidine compounds: 3b-hydroxypregn-5-ene-20-one derivatives

In continuation of our research for synthesizing heterocyclic derivatives with a broad range of biological activities, the current research was performed to synthesize 3 ss-hydroxypregn-5-ene-20-one derivatives of coumarin, isoxazole, pyrazole, pyridine and pyrimidine and screen for antitumor activity. Synthesis of amino-thiophene derivatives (1a-1b) was performed through a reaction of 3 ss-hydroxypregn5-ene-20-one with ethyl cyanoacetate or malononitrile and sulfur. 3 ss-Hydroxypregn-5-ene-20-one was reacted with ethyl cyanoacetate in the presence of hydrazine, urea, or thiourea to obtain aminopyrazole (3), aminopyrimidine (4a-4b) derivatives, respectively. The amino-thiophene derivatives (1a-1b) further reacted with either phenylisothiocyanate or benzoylisothiocyanate to form fused thienopyrimidine derivatives (5a-5d). The products 1a and 1b were also treated with ethyl cyanoacetate to afford cyanoacetamidothiophene derivatives (6a-6b) which were converted to fused thienopyridone derivatives (7a-7b) through cyclization reaction. The compounds 6a and 6b were allowed to react with different carbonyl compounds including salicyaldehyde, cyclopentanone-sulfur mixture, acetylacetone, and malonaldehyde to prepare coumarin (8a-8b), cyclopentylthiophene (9a-9b) and 2-pyridinone (10a-10d) derivatives, respectively. Furthermore, the reactions of hydroxylamine hydrochloride and benzoylacetonitrile with the compounds 6a-6b separately afforded new aminoisoxazole (12a-12b) and phenylpyridone (14a-14b) derivatives, respectively. The structures of new products were established through IR, H-1 NMR, C-13 NMR spectroscopic, and mass spectrometric analysis. The synthesized compounds (1a-1b to 14a-14b) displayed in-vitro antitumor activity against human cell lines, including MCF-7 (breast adenocarcinoma), SF-268 (CNS cancer) and NCI-H460 (non-small lung cancer cells). The results suggested that all the screened products exhibited cell growth inhibitory activity in a dose-dependent manner. However, compound 12a showed the highest level of inhibition against all three cell lines.