Antiproliferative and antibacterial activity of 3-arylbenzo[g]indazoles functionalized with nitro and amino groups at position 6

Indazoles are benzo-fused pyrazoles for which a broad range of biological properties have been described, including antiproliferative and antibacterial activities. These fused tricyclic pyrazole derivatives are characterized by their conformational restriction. As part of our ongoing project on conformationally restricted ligands interacting at the colchicine binding site in tubulin [1], we have here designed and synthesized a novel series of tricyclic pyrazoline derivatives incorporating a nitro or an amino group at position 6 on the benzo[g]indazol ring and different aryl groups at position 3. The expected (3R,3aS)-rel- and (3R,3aR)-rel-isomers were obtained by reaction of the 5-nitro benzylidene tetralones with hydrazine in acetic acid. The 3D geometries of both isomers were optimized showing that in the (3R,3aR)-rel-isomer one of the hydrogens at position 4 is facing the phenyl ring, and thus this proton is shielded and appears in the ¹H NMR spectra around at δ=0.7-0.8 ppm in the whole series. These conformationally constrained compounds were evaluated for their antiproliferative activity against selected cancer cell lines. Some nitro-based indazoles have shown IC₅₀ values between 5-10 μM against the lung carcinoma cell line NCI-H460. Moreover, two of the here synthesized compounds have shown MIC values of 250 and 62.5 μg/mL against N. gonorrhoeae with no hemolytic activity in human red blood cells (RBC).

Acknowledgements: V.C., M.P.C. and B.I. thank the Universidad del Valle (CIAM-2017), COLCIENCIAS and the Science, Technology and Innovation Fund-General Royalties System (FCTeI-SGR) under contract BPIN 2013000100007, Colombia. M.-J. P.-P., E.-M. P. and M.-J. C. acknowledge the financial support of SAF2015-64629-C2-1-R and CSIC-PIE-201680E079

Reference

[1] Bueno, O.; Tobajas, G.; Quesada, E.; Estévez-Gallego, J.; Noppen, S.; Camarasa, M. J.; Díaz, J. F.; Liekens, S.; Priego, E. M.; Pérez-Pérez, M. J. Conformational Mimetics of the α-Methyl Chalcone TUB091 Binding Tubulin: Design, Synthesis and Antiproliferative Activity. Eur. J. Med. Chem. 2018, 148, 337–348. https://doi.org/10.1016/j.ejmech.2018.02.019.