3-(Difluoromethyl)cinnamic acid amides with antibacterial activity

MARTINEZ, MARIO D.; DURÁN, FERNANDO J.; MORA VERÓNICA; BERTONCELLO, LUCILA; ZINI, ELVIRA; BURTON, GERARDO

Amsterdam

Simposio; 13th Tetrahedron Symposium; 2012

Elsevier Science

Infectious diseases with Multi-Drug-Resistant strains have arisen as a critical situation worldwide, tuberculosis being a major threat that requires new antimycobacterial agents active on Mycobacterium tuberculosum  resistant strains.1 Mono and dihydroxy trans-cinnamic acid amides have attracted much attention due to their effective antibacterial action but most of the synthetic modifications have focused on the amide side-chain and the introduction of substituents at the phenolic hydroxyl.2 Our approach was to prepare and evaluate a series of amides derived from caffeic acid carrying a bioisosteric replacement of the phenolic 3-hydroxyl for a difluoromethyl group. This would increase the lipophylicity while still maintaining hydrogen bond donor and acceptor capacity in that region of the molecule. The modification of the caffeic acid skeleton and subsequent formation of the amides was achieved by a straightforward methodology consisting of a one-pot triple transformation of intermediate 2, that may be used to obtain a wide variety of amides. Regioselective iodination of o-anisaldehyde (1), followed by a Heck coupling with methyl acrylate and hydrolysis gave the intermediate 2. The key step was carried out in two stages, first the oxoacid 2 was treated with bis(2-methoxyethyl)aminosulfur trifluoride (Deoxofluor®) to give 3. The reaction mixture was then percholated through silica gel to remove byproducts of the fluorination reagent and the acyl fluoride solution was treated with the desired amine in the presence of triethylamine to give the corresponding amides 4a-l. Minimum inhibitory concentrations (MIC) were measured against a panel of 14 microorganisms (Gram + and -). The 3-(difluoromethyl)cinnamyl amides 4c, 4e and 4j were the most active exhibiting high selectivity against Mycobacterium smegmatis (MIC 8 mg/ml). In addition, a series of N-isopropylamides (5-9) analogs of 4e, were prepared to provide an insight on structure-activity relationships. Compound 4e being more active (4× or more) in all cases