Synthesis, computational investigation and biological evaluation of α,α-difluoromethyl ketones embodying pyrazole and isoxazole nuclei as COX inhibitors.
Org Biomol Chem
; 20(42): 8293-8304, 2022 Nov 02.
Article
in En
| MEDLINE
| ID: mdl-36227250
ABSTRACT
α,α-Difluoromethyl ketones (DFMKs) have emerged as currently investigated agents benefiting from the merging of chemico-physical features conferred by the constitutive elements (-CHF2 and carbonyl moietites). With a view to biological applications, the additional incorporation of heterocycles is a desirable property enabling the tuning of critical factors encompassing the pharmaco-dynamic and kinetic profiles. The underexplored assembling of α,α-difluoromethyl-heteroaromatic ketones is herein implemented via a conceptually intuitive Weinreb amide acylative transfer of a putative difluoromethyl-carbanion. To make the strategy productive, we adopted the commercially available TMSCHF2 pronucleophile - characterized by robust chemical stability and manipulability (bp 65 °C) - which upon Lewis-base mediated activation delivers the competent CHF2-nucleophile. The synthetic protocol was carried out on pyrazole- and isoxazole-based scaffolds, and a panel of heteroaryl-DFMKs was consequently developed as potential COX-inhibitors. In this sense, the bioisosterism deducted through docking studies between the widely expressed carboxylic group (in several clinically used COX inhibitors) and the -COCHF2 motif introduced herein supports this rationale. To confirm the docking results, all compounds were tested against both COX-1 and COX-2 enzyme isoforms showing activity in the micromolar range and a good selectivity index (SI). They were also evaluated for their biocompatibility using NIH/3T3 cells to which they did not show any significant toxicity.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Isoxazoles
/
Ketones
Type of study:
Guideline
Limits:
Animals
Language:
En
Journal:
Org Biomol Chem
Journal subject:
BIOQUIMICA
/
QUIMICA
Year:
2022
Document type:
Article
Affiliation country:
Italia