Objectives: Many natural antioxidants have poor pharmacokinetic properties that impair their therapeutic use. For hydroxycinnamic acids (HCAs) and other phenolic antioxidants, their major drawback is their low lipophilicity and a rapid metabolism. The difluoromethyl group may be considered as a ‘lipophilic hydroxyl' due to its hydrogen bond donor and acceptor properties; this prompted us to assess it as a bioisosteric replacement of a phenolic hydroxyl for increasing the lipophilicity of HCAs. Methods: Six difluoromethyl-substituted methyl cinnamates (4a-c, 5a-c) related to caffeic acid were synthesized and their antioxidant activity evaluated by chemical (FRAP, DPPH scavenging, inhibition of β-carotene bleaching, at 1–200 μm), electrochemical (differential pulse voltammetry, cyclic voltammetry) and cell-based (inhibition of lipid peroxidation in erythrocytes, at 1 and 50 μm) assays. Key fndings: Analogues 4a-c and 5a-c were inactive in FRAP and DPPH assays and only those containing a free phenolic hydroxyl (4a and 5a) exhibited electrochemical activity although with high redox potentials. Compounds 4a,b and 5a,b were active in the inhibition of β-carotene bleaching assay and all analogues inhibited lipid peroxidation in the human erythrocytes assay. Conclusions: Lipophilic difluoromethyl-substituted cinnamic esters retain radical scavenging capabilities that prove useful to confer antioxidant properties in a non-polar environment.

An innovative approach to position‐selective polyhalogenation of aliphatic hydrocarbon bonds is presented. The reaction proceeded within the Hofmann‐Löffler manifold with amidyl radicals as the sole mediators to induce selective 1,5‐ and 1,6‐hydrogen‐atom transfer followed by halogenation. Multiple halogenation events of up to four innate C−H bond functionalizations were accomplished. The broad applicability of this new entry into polyhalogenation and the resulting synthetic possibilities were demonstrated for a total of 27 different examples including mixed halogenations.

Series of novel amides of isoferulic acid, where the phenolic hydroxyl was replaced by a difluoromethyl group, were synthesized and their in vitro antibacterial activities assayed against fourteen bacterial strains (six Gram-positive and eight Gram-negative). A one-pot methodology was developed to obtain the 3′-(difluoromethyl)-4′-methoxycinnamoyl amides using Deoxofluor^® as a fluorinating agent. The N-isopropyl, N-isopentyl, and N-(2-phenylethyl) amides 11b, 11d and 11g were the most active and selective against Mycobacterium smegmatis (MIC = 8 µg/mL) with 11b and 11g displaying negligible or no cytotoxicity against HepG2 and A549 cells. Thirteen analogs of N-isopropylamide 11b were also synthesized and their antibacterial activity assayed. Results show that the difluoromethyl moiety enhanced antibacterial activity and selectivity towards M. smegmatis, changing the microorganism inhibition profile of the parent compound. The selectivity exhibited by some of the compounds towards M. smegmatis makes them potential leads in the search for new narrow spectrum antibiotics against M. tuberculosis.