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Antiproliferative and antibacterial activity of 3-arylbenzo[g]indazoles functionalized with nitro and amino groups at position 6
* 1, 2 , 3 , 4 , 5 , 5 , 4 , 1, 2 , 4
1  Grupo de Investigación de Compuestos Heterocíclicos, Departamento de Química, Universidad del Valle, A. A. 25360 Cali, Colombia
2  Centre for Bioinformatics and Photonics-CIBioFI, Calle 13 No. 100-00, Edificio E20, No. 1069, Cali, Colombia
3  Grupo de Biotecnología e Infecciones Bacterianas, Departamento de Microbiología, Universidad del Valle, Cali, Colombia
4  Instituto de Química Médica (IQM-CSIC), Juan de la Cierva 3, 28006-Madrid, Spain
5  KU Leuven Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute for Medical Research, KU Leuven, Herestraat 49, 3000 Leuven, Belgium

Published: 30 October 2019 by MDPI in 5th International Electronic Conference on Medicinal Chemistry session Posters

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


[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.

Keywords: Indazole; 2-benzylidene-1-tetralone; antiproliferative activity; antibacterial activity