Microwave-assisted and continuous flow multistep synthesis of 4-(pyrazol-1-yl)carboxanilides.

A series of 4-(pyrazol-1-yl)carboxanilides active as inhibitors of canonical transient receptor potential channels were synthesized in an efficient three-step protocol using controlled microwave heating. The general synthetic strategy involves condensation of 4-nitrophenylhydrazine with appropriate 1,3-dicarbonyl building blocks, followed by reduction of the nitro group to the amine, which is then amidated with carboxylic acids. Compared to the conventional protocol a dramatic reduction in overall processing time from ~2 days to a few minutes was achieved, accompanied by significantly improved product yields. In addition, the first two steps in the synthetic pathway were also performed under continuous flow conditions providing similar isolated product yields. As an alternative to the three-step protocol, a novel two-step route to the desired 4-(pyrazol-1-yl)carboxanilides was devised involving condensation of 4-bromophenylhydrazine with appropriate 1,3-dicarbonyl building blocks, followed by Pd-catalyzed Buchwald-Hartwig amidation with carboxylic acid amides.

Designs and syntheses of oxathiin carboxanilide analogues and their antiviral activities.

Syntheses of new analogues of oxathiin carboxanilide (UC84) and their antiviral activities were described. The heterocyclic carboxylic acids including oxathiins (4), thiazines (9) and dithiins (13) in which the methyl was replaced either by lipophilic trifluoromethyl- or bulky phenyl-group were synthesized starting from beta-keto esters (5). Reaction of 4, 9 and 13 with thionyl chloride followed by treatment of the substituted aniline 22 gave the corresponding carboxanilides (24a-24f). The carboxanilides were subjected to Laweson's reagent the corresponding thiocarboxanilides (24g-24k). The antiviral activities of the synthesized compounds against human immunodeficiency virus type 1 (HIV-1), poliovirus type 1 (PV-1), coxsackie B virus type 3 (CoxB-3), vesicular stomatitis virus (VSV) and herpes simplex virus type 1 (HSV-1) were presented. The antiviral activity against HIV-1 of dithiin carboxanilide (24e) was similar with that of UC84 (24a). The corresponding thiocarboxanilides (24g-24k) showed higher inhibitory activity against HIV-1 than the carboxanilides (24a, 24b, 24d, 24e). The compounds in which ether the lipophilic trifluoromethyl substituents (24d, 24f, 24i, 24k) or bulky phenyl substituent is present in the heterocyclic compounds showed lower inhibitory activity than that of the methyl substituents is present in the compounds against the HIV-1. But the trifluoromethylated dithiin (24f) showed higher inhibitory activity against PV-1 and CoxB-3 virus than commercial antiviral agents, ribavirin (RV).

Reaction site of carboxanilides and of thenoyltrifluoroacetone in complex II.

Oxathiin carboxanilides are systemic fungicides that inhibit the oxidation of succinate by interrupting electron transport between succinate dehydrogenase [succinate:(acceptor) oxidoreductase, EC 1.3.99.1] and coenzyme Q. Kinetic and electron paramagnetic resonance studies have established that the specific binding site of carboxanilides and of thenoyltrifluoroacetone responsible for the inhibition is the same. Although the binding of carboxanilides to membrane preparations of the dehydrogenase is very tight (Ki = 0.01-0.1 microM), it is noncovalent. Identification of the membrane component(s) to which specific binding occurs has therefore required the introduction of a photoaffinity label onto the carboxanilide molecule. By using [G-3H]3'-azido-5,6-dihydro-2-methyl-1,4-oxathiin-3-carboxanilide, it was found, in accord with earlier data with other carboxanilides, that unresolved complex II specifically binds about 0.6 mol of the inhibitor per mol of succinate dehydrogenase in equilibrium dialysis experiments. The resolved components of the complex, succinate dehydrogenase and the two binding peptides CII-3 and CII-4, failed to bind the inhibitor; however, when these were recombined with reconstitution of coenzyme Q reductase activity, the initial binding titer was restored. Azidocarboxanilide-inhibited complex II was irradiated to generate covalent linkages with the binding site, and the components of the complex were separated on polyacrylamide gel. Most of the specifically bound inhibitor was found in the low molecular weight binding peptides and phospholipids.