Synthesis, computational investigation and biological evaluation of α,α-difluoromethyl ketones embodying pyrazole and isoxazole nuclei as COX inhibitors

Abstract

α,α-Difluoromethyl ketones (DFMKs) emerged as currently investigated agents benefiting from the merging of chemico-physical features conferred by the constitutive elements (-CHF2 and carbonyl moietites). With vistas to biological applications, the...

Syntheses, reactivity, and biological applications of coumarins

“…Radical and photochemical approaches were also investigated en route to the introduction of fluorinated functionalities in position 3 of the coumarin system. Difluoromethylation today represents a straightforward manner to tune physico-chemical properties of pharmaceuticals and several research groups attempted to selectively incorporate this relevant functional group into bioactive compounds ( Swallow, 2015 ; Miele et al, 2019 ; Citarella et al, 2022 ). Sun and collaborators realized a simple silver-catalyzed oxidative decarboxylation of arylthiodifluoroacetic acids or aryloxydifluoroacetics ( 77 ) for the selective C-3 functionalization of coumarins ( 76 ) with a difluoromethyl group ( Scheme 4 — path b ) ( Sun et al, 2022 ).…”

“…Traditional NSAIDs with higher selectivity for COX-1 cause greater gastrointestinal bleeding, ulcer, and renal toxicity than those selectively targeting COX-2. Consequently, several studies led to the development of selective inhibitors of COX-2 isoform (coxibs) ( Citarella et al, 2022 ). A new series of pyrimidine-5-carbonitrile-based coumarin derivatives was synthesized by Alfayomy et al and their inhibitory activity was evaluated on both COX-1 and COX-2 ( Alfayomy et al, 2021 ).…”

Recent Advances in SARS-CoV-2 Main Protease Inhibitors: From Nirmatrelvir to Future Perspectives

“…Normally, they act as reversible covalent inhibitors toward the target but, in their hydrated form, they can also act as transition-state competitive analogues [2]. Citarella et al synthetized a new dipeptidyl DFMK as a SARS-CoV-2 M pro inhibitor (i.e., compound 52; Figure 33) [67], based on the corresponding TFMKs SARS-CoV M pro inhibitor reported by Shao et al, using a direct and chemoselective difluoromethyl unit transfer reaction [68,69]. Compound 52 bears a Cbz-Leu-HomoPhe sequence as a peptide framework linked to a C-terminal DFMK moiety.…”

Cyrene: A Green Solvent for the Synthesis of Bioactive Molecules and Functional Biomaterials

“…Fluorinated moieties are, nowadays, becoming increasingly popular thanks the interesting properties that the fluorine atom can impart to the molecule (bioiso biocompatibility, improvement of metabolic parameters, inter alia) [27], and the re furnished to the obtained structure which can undergo further functionalizati Among the structural modifications in which fluorine can play a significant r difluoromethyl group (-CHF2) has increasingly established itself in the chemi pharmaceutical panorama [29]; therefore, novel methods of difluoro functionalization are becoming necessary. In particular, the use (difluoromethyl)trimethylsilane (TMSCHF2) reagent, in the presence of a base KOH or alkoxyde, currently represents one of the most appealing sources difluoromethyl group [30][31][32]. Quero and coworkers combined the use of the synthesized CuI/BNNSs (copper iodide nanoparticles/boron nitride nanosheets) s as heterogenous catalysts for the -CH difluoromethylation reaction of heteroare terminal alkynes, and the green reaction medium Cyrene, instead of the common NMP (Scheme 10) [33].…”

“…Among the structural modifications in which fluorine can play a significant role, the difluoromethyl group (-CHF 2 ) has increasingly established itself in the chemical and pharmaceutical panorama [29]; therefore, novel methods of difluoromethyl functionalization are becoming necessary. In particular, the use of the (difluoromethyl)trimethylsilane (TMSCHF 2 ) reagent, in the presence of a base such as KOH or alkoxyde, currently represents one of the most appealing sources of the difluoromethyl group [30][31][32]. Quero and coworkers combined the use of the newly synthesized CuI/BNNSs (copper iodide nanoparticles/boron nitride nanosheets) supports as heterogenous catalysts for the -CH difluoromethylation reaction of heteroarenes and terminal alkynes, and the green reaction medium Cyrene, instead of the common DMF or NMP (Scheme 10) [33].…”