Antioxidant properties in a non-polar environment of difluoromethyl bioisosteres of methyl hydroxycinnamates

Abstract

Lipophilic difluoromethyl-substituted cinnamic esters retain radical scavenging capabilities that prove useful to confer antioxidant properties in a non-polar environment.

Difluoromethyl Bioisostere: Examining the “Lipophilic Hydrogen Bond Donor” Concept

“…In particular, replacing a methyl with the difluoromethyl group may lead to a smaller lipophilicity increase relative to trifluoromethyl , and provides new hydrogen bonding ability (Figure A). There are many examples exhibiting involvement of hydrogen bond donating interactions of this group at the active site. − Therefore, it is regarded as a possible “lipophilic hydrogen bond donor” moiety or in other words as a “lipophilic bioisostere” of hydroxyl (OH) and thiol (SH) functional groups. − It should be noted though that the hydrogen bonding of this group has not been studied systematically yet and is estimated to be relatively weak. For example, in a CH···O interaction, it has been estimated by calculations that each fluorine adds about 1 kcal/mol to the binding energy …”

Synthesis and Antibacterial Activity of Difluoromethyl Cinnamoyl Amides

“…These results suggest that the balance between lipophilicity (see Table S1) and hydrogen bond donor/acceptor capacities of the CF 2 H moiety is a significant contributor to the observed activity and selectivity towards M. smegmatis of the N-isopropylamide derivative. Furthermore, to analyze the aromatic ring substitution pattern, the regioisomer 15 was obtained from the methyl cinnamate 14 (Scheme 3) [26]. Compound 15 presented a different antibacterial activity profile (MIC = 32 µg/mL against Clostridium sporogenes, see Table 2) compared to compound 11b, proving the importance of the substitution pattern in the selective activity against Mycobacterium smegmatis.…”

“…5-Iodo-2-methoxybenzaldehyde was obtained by iodination of 2-methoxybenzaldehyde with iodine/silver nitrate in methanol [28]. Methyl-3-[4-formyl-3-methoxyphenyl]-(E)-propenoate (14) was obtained as described previously [26]. 6-Methoxy-3,4-dihydronaphthalene-2-carboxylic acid was obtained from commercial 6-methoxytetralone [41].…”

“…Previously, we also found an interesting bioisosteric relationship in the antioxidant behavior between difluoromethyl substituted arenes and phenols. Thus, replacement of a phenolic hydroxyl by a difluoromethyl moiety on hydroxycinnamic acid methyl ester scaffolds conferred radical scavenging ability only in lipophilic environments, even in the absence of free phenol groups, probably due to a hydrogen atom transfer mechanism [26]. We envisaged that the combination of this lipophilicity-booster fluorinated moiety together with the amidation strategy applied to HCAs could lead to analogs with enhanced ADME properties, with the added possibility of perturbing the bacterial redox homeostasis beyond the effects over the bacterial cell wall.…”

Base-Promoted Radical Azofluoromethylation of Unactivated Alkenes

“…In contrast to various methods for the synthesis of trifluoromethylated organic substrates, direct difluoromethylation is still underdeveloped, 53−63 albeit the difluoromethyl group (CF 2 H) is an intriguing structural motif in drug design. 64,65 We are glad to find that our protocol can also be applied to the azodifluoromethylation of alkenes by just switching the Langlois' reagent with the commercially available Table 1. Reaction Conditions for the Optimization of the Azotrifluoromethylation of Alkenes a a Unless otherwise noted, reactions were conducted with a solution of 2a (2 equiv) in 200 μL of mixed solvent (DMF/H 2 O = 3/1) added dropwise to the mixture 1a (0.2 mmol), base (0.5 equiv), and 3 (2 equiv) in 800 μL mixed solvent (DMF/H 2 O = 3/1) at −10 °C; the reaction was then stirred at rt for 1 h. b Yields were determined by 19 F NMR using 4-fluoroanisole as an internal standard.…”