Multi-targeting derivatives of (±)-aminoglutethimide: Synthesis, anti-leishmanial, cytotoxicity against cancerous cells and molecular docking studies

During the current study, we have synthesized 15 (8a-o) new substituted benzylamine analogs of (±)-aminoglutethimide (6) by using standard methods being employed in organic syntheses. Purification of the synthesized compounds was carried out by using normal phase column chromatography, followed by characterization by using state-of-the-art, NMR, UV, and IR spectroscopic techniques along with low and high resolution mass spectrometry. The compounds were evaluated for their cytotoxic effects against normal and breast cancer cells, including 3T3 normal, MCF-7, MDA-MB-231 Breast cancer, and HeLa Cervical cancer cell lines. Compound 8l exhibited more significant activity with IC50 = 8.15 ±  0.42 µM. Similarly, compounds 8e (IC50 = 19.11 ±  0.39 µM), 8h (IC50 = 14.7 ±  0.17 µM), 8i (IC50 = 12.82 ±  0.24 µM), and 8j (IC50 = 19.87 ±  0.14 µM) also exhibited significant toxicity against cancer cell line (MDA-MB-231). Compound 8e (IC50 = 22.4 ±  0.5 µM), 8j (IC50 = 17.2 ±  1.2 µM), and 8m (IC50 = 17.6 ±  0.4 µM), showed significant inhibition of HeLa cells, while compound 8j (IC50 = 14.08 ±  0.19 µM) was active towards MCF-7 cancer cells. These compounds also showed significant activity against L. major, except compounds 8d and 8n. To compare the result standard anti-leishmanial drug miltefosine was used (IC50 = 25.5 ±  0.42 µM). Interestingly, it was observed that all compounds were significantly active while compared with amphotericin B (IC50 = 3.39 ±  0.04 µM), another standard drug used for the treatment of leishmaniasis. Compounds 8e, 8j-k and m-n were significantly active against promastigotes L. tropica, (amphotericin B = IC50 = 3.41 ±  0.84 µM). In silico studies predicted the interactions of compounds 8a-o with multiple therapeutically relevant leishmanial enzymes, such as pteridine reductase (PTR1), N-methyltransferase (NMT), and MAP kinase (MAPK) that are crucial for the survival of parasite. The cytotoxicity of all compounds was also evaluated against normal cell line (3T3). Compounds were found to be non-toxic against normal cells except 8e, i, j, and m.