Synthesis and Biological Evaluation of New Functionalized Nitroindazolylacetonitrile Derivatives. Issue 48 (20th December 2019)

• Record Type: Journal Article
• Authors: Eddahmi, Mohammed; Moura, Nuno M. M.; Bouissane, Latifa; Faustino, Maria A. F.; Cavaleiro, José A. S.; Paz, Filipe A. A.; Mendes, Ricardo F.; Figueiredo, Joana; Carvalho, Josué; Cruz, Carla; Neves, Maria G. P. M. S.; Rakib, El Mostapha
• Is Part Of: ChemistrySelect. Volume 4:Issue 48(2019)
• Page Start: 14335
• Page End: 14342
• Publication Date: 2019-12-20
• Subjects: Alkylation -- Cancer -- Knoevenagel Condensation -- Nitroindazolylacetonitriles -- Pinner Reaction; Chemistry -- Periodicals; 540.5
• DOI: 10.1002/slct.201904344
• Languages: English
• ISSNs: 2365-6549

Abstract

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. Abstract : Nitroindazolylacetonitriles showed to be excellent templates to be further functionalized by alkylation, Knoevenagel condensation and cascade Knoevenagel/Pinner approaches. These synthetic methodologies allowed to prepare a series of new functionalized N‐methyl‐nitroindazole derivatives in good to excellent yields. None of the compounds violated the Lipinski's Rule of Five and the antiproliferative effect towards HeLa cancer cells and non‐malignant cells was evaluated.