In Vitro Anti-Candida Activity and Action Mode of Benzoxazole Derivatives

A newly synthetized series of N-phenacyl derivatives of 2-mercaptobenzoxazole, including analogues of 5-bromo- and 5,7-dibromobenzoxazole, were screened against Candida strains and the action mechanism was evaluated. 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-bromophenyl)ethanone (5d), 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,3,4-trichloro-phenyl)ethanone (5i), 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,4,6-trichlorophenyl)ethanone (5k) and 2-[(5-bromo-1,3-benzoxazol-2-yl)sulfanyl]-1-phenylethanone (6a) showed anti-C. albicans SC5314 activity, where 5d displayed MICT = 16 µg/mL (%R = 100) and a weak anti-proliferative activity against the clinical strains: C. albicans resistant to azoles (Itr and Flu) and C. glabrata. Derivatives 5k and 6a displayed MICP = 16 µg/mL and %R = 64.2 ± 10.6, %R = 88.0 ± 9.7, respectively, against the C. albicans isolate. Derivative 5i was the most active against C. glabrata (%R = 53.0 ± 3.5 at 16 µg/mL). Benzoxazoles displayed no MIC against C. glabrata. Benzoxazoles showed a pleiotropic action mode: (1) the total sterols content was perturbed; (2) 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(3,4-dichlorophenyl)ethanol and 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,3,4-trichlorophenyl)ethanol (8h–i) at the lowest fungistatic conc. inhibited the efflux of the Rho123 tracker during the membrane transport process; (3) mitochondrial respiration was affected/inhibited by the benzoxazoles: 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-chlorophenyl)ethanol and 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-bromophenyl)ethanol 8c–d and 8i. Benzoxazoles showed comparable activity to commercially available azoles due to (1) the interaction with exogenous ergosterol, (2) endogenous ergosterol synthesis blocking as well as (3) membrane permeabilizing properties typical of AmB. Benzoxazoles display a broad spectrum of anti-Candida activity and action mode towards the membrane without cross-resistance with AmB; furthermore, they are safe to mammals.

Phenacylation of 6-Methyl-Beta-Nitropyridin-2-Ones and Further Heterocyclization of Products

Reaction between the derivatives of 6-methyl-beta-nitropyridin-2-one and phenacyl bromides was studied, and the yields observed were extremely low. The pyridones were converted via chloropyridines to methoxyderivatives, which were N-phenacylated. N-Phenacyl derivatives of 4,6-dimethyl-5-nitropyridin-2-one under the action of base gave 5-hydroxy-8-nitroindolizine and under acidic conditions gave 5-methyl-6-nitrooxazole[3,2-a]pyridinium salt, which underwent recycization with MeONa to 5-methoxy-8-nitroindolizine.

Synthesis of substituted pyrrolo[2,3-d]pyrimidines and pyrido[2,3-d]pyrimidines in the one-pot condensation of 2-thio-6-aminouracil, arylglyoxals and CH-acids

We have developed some available and effective methods for the synthesis of substituted pyrrolo[2,3-d]pyrimidines and 5,8-dihydropyrido[2,3-d]pyrimidines based on the three-component condensation of 6-amino-2-thiouracil with arylglyoxal hydrates and N,N-dimethylbarbituric acid or acyclic β-dicarbonyl compounds: acetylacetone (acetoacetic ester). It was shown that the optimal product yields were obtained by boiling the reagents in acetic acid. Thus, the synthesis of pyrrolo[2,3-d]pyrimidines took 15-20 minutes, while the precipitation of 5,8‑dihydropyrido[2,3-d]pyrimidines formed only after 2 hours. We proposed possible mechanisms for the formation of anelated pyrrole and pyridine rings. In both cases, the reaction includes the formation of an intermediate of α,β-unsaturated ketone with the participation of arylglyoxal and CH-acid (N,N-dimethylbarbituric or acetylacetone (acetoacetic ester)), nucleophilic addition of 6-aminothiouracil via an activated double bond, condensation of carbonyl and amino groups. The formation of the cycle takes place exclusively with the participation of the acetyl moiety, while the pyrrol one forms during the condensation of the aroyl moiety and the 6-amino group of thiouracil. A series of synthesized pyrrolo[2,3-d]pyrimidines was modified by alkylation. As it was expected, alkylation proceeds at the sulfur atom, that allowed a significant increase in the solubility of the obtained products. The reaction was carried out in DMF by stirring the initial reagents at 60ºC (reaction with methyl iodide) or boiling them (alkylation with phenacyl bromide), whereby S-methyl and S-phenacyl derivatives of pyrrolo[2,3-d]pyrimidines were obtained. The spectral data of 1H NMR showed that S-methylation products form solvates with DMF as 1:1. The synthesized compounds can become the basis to create small libraries of anelated pyrimidines with improved antiviral activity profile.