abstract
The versatility of N-methyl-nitroindazolylacetonitriles as templates for further modifications was evidenced by their successfully alkylation with a series of alkyl halides using DBU as base affording the monoalkylated derivatives in high yields. Another synthetic strategy used to modify the nitroindazolylacetonitrile derivatives was the Knoevenagel condensation with a series of aldehydes in the presence of piperidine; such condensation allowed the preparation of the desired products in good to excellent yields. The reaction of a series of nitroindazolylacetonitriles with salicylaldehyde showed to be an efficient and fast methodology to prepare chromenone-imine-indazoles (83-92%), which by acid hydrolysis were converted into the corresponding chromenone-indazole derivatives (88-94%). The structures of derivatives 8 h, 8 l and 10 were unequivocally confirmed by single crystal X-ray diffraction. The drug-likeness properties of the compounds were evaluated in silico and none of the tested nitroindazolylacetonitriles violated the Lipinski's rule of five. The antiproliferative activity against human cervical cancer cells (HeLa) and normal human dermal fibroblasts was evaluated by MTT assay and revealed that compounds 7 b, 8 d and 14 a are those who presented higher antiproliferative effect against HeLa cancer cells.
keywords
INDAZOLE DERIVATIVES; INHIBITORS; POTENT; OPTIMIZATION; SOLUBILITY; SYNTHASE
subject category
Chemistry
authors
Eddahmi, M; Moura, NMM; Bouissane, L; Faustino, MAF; Cavaleiro, JAS; Paz, FAA; Mendes, RF; Figueiredo, J; Carvalho, J; Cruz, C; Neves, MGPMS; Rakib, E
our authors
acknowledgements
Thanks are due to the University of Aveiro and FCT/MCTES for the financial support for the QOPNA research Unit (FCT UID/QUI/00062/2019) through national founds (OE) and, where applicable, co-financed by the FEDER, within the PT2020 Partnership Agreement, and to the Portuguese NMR Network. The authors also thank CICECO-Aveiro Institute of Materials (FCT UID/CTM/50011/2019), Sultan Moulay Slimane University and the Transnational cooperation programs, FCT-CNRST (Morocco), for financial assistance (2019-2020). NMM Moura thanks his research contract (CDL-CTTRI-88-89-97-ARH/2018) which is funded by national funds (OE), through FCT - Fundacao para a Ciencia e a Tecnologia, I.P., in the scope of the framework contract foreseen in numbers 4, 5 and 6 of the article 23, of the Law Decree 57/2016, of August 29, changed by Law 57/2017, of July 19. RF Mendes gratefully acknowledges FCT for a Junior Research Position (CEECIND/00553/2017). J Carvalho and J Figueiredo acknowledge fellowship grants ref. SFRH/BD/122953/2016 and PINFRA/22161/2016 PTNMR, respectively. C. Cruz acknowledges the funding from projects BIODEVICE ref. MIT-EXPL/BIO/0008/2017, DREAM ref. UTAP-EXPL/NTec/0015/2017 and project IF/00959/2015.