Dermatomycoses are among the most widespread and common superficial and cutaneous fungal infections in humans. There is an urgent need to develop efficient and non-toxic antimycotic agents with a specific spectrum of activity. Triterpenes have been demonstrated to exhibit a wide range of biological activities, including antifungal activities. In this study, through hemisynthesis, we aimed to obtain triterpene-isosteric molecules from betulinic and ursolic acids to improve the antifungal activity and spectrum of action of these compounds. Six compounds were resynthesized and tested against eleven mucocutaneous and cutaneous mycotic agents. The results of the susceptibility assays were expressed as the minimal inhibitory concentration (MIC). The MIC values of the piperazinyl derivatives of ursolic and betulinic acids that were active against pathogenic yeasts were in the range of 16-32 μg/mL and 4-16 μg/mL, respectively, whereas fungicidal effects were observed at concentrations ranging from 16 to 128 μg/mL and 8 to 128 μg/mL, respectively. The piperazinyl derivative of betulinic acid exhibited an antifungal profile similar to that of terbinafine and was the most effective derivative against dermatophytes. This strategy led to a promising candidate for the development of a new antifungal agent.

The present study investigates the antinociceptive effect of the pyrazolyl-thiazole derivative 2-(5-trichloromethyl-5-hydroxy-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-4-(4-bromophenyl)-5-methylthiazole (B50) in mice. Male albino Swiss mice (30-40 g) were used in the acetic acid-induced abdominal writhes and tail-immersion tests. B50 caused dose-dependent antinociception (8, 23 and 80 µmol/kg, sc) in the acetic acid writhing assay (number of writhes: vehicle: 27.69 ± 6.15; B50 (8 µmol/kg): 16.92 ± 3.84; B50 (23 µmol/kg): 13.85 ± 3.84; B50 (80 µmol/kg): 9.54 ± 3.08; data are reported as means ± SEM for 9 animals per group). On the other hand, B50 did not cause antinociception in the tail immersion assay. Naloxone (2.75 µmol/kg, sc) prevented B50-induced antinociception (number of writhes: vehicle-saline: 31.11 ± 3.15; vehicle-naloxone: 27.41 ± 3.70; B50 (80 µmol/kg)-saline: 8.70 ± 3.33; B50 (80 µmol/kg)-naloxone: 31.84 ± 4.26; morphine-saline: 2.04 ± 3.52; morphine-naloxone: 21.11 ± 4.26; 8-9 animals per group). The removal of the methyl group of the thiazole ring of B50 or substitution of the bromo substituent with the methyl at position 4 of the phenyl group, which is attached to the thiazole ring of B50, resulted in loss of activity, suggesting that these substituents are important for antinociceptive activity. B50 had no effect on spontaneous locomotion or rotarod performance, indicating that the antinociceptive effect of B50 is not related to nonspecific motor effects. The antinociceptive profile of B50 seems to be closer to nonsteroidal anti-inflammatory drugs than to classic opioid agents, since it had no analgesic effect in a thermally motivated test. Key wordsThe pyrazole ring is a heterocycle compound containing two contiguous nitrogen atoms and three carbon atoms. Until 1995, in a few cases, only 5-trifluoromethyl-5-hydroxy-1H-pyrazolines and pyrazolidines could be synthesized, and pyrazolines other than 5-trifluoromethylated ones had been detected only by special nuclear magnetic resonance techniques (1). In 1999, Bonacorso et al. (2) described for the first time the synthesis and structural elucidation by nuclear magnetic resonance, Austin Model 1 calculations and X-ray diffraction of a novel series of twelve 3-aryl(alkyl)-5-hydroxy-1-

Emerging yeasts are among the most prevalent causes of systemic infections with high mortality rates and there is an urgent need to develop specific, effective and non-toxic antifungal agents to respond to this issue. In this study 35 aldehydes, hydrazones and hydrazines were obtained and their antifungal activity was evaluated against Candida species (C. parapsilosis, C. tropicalis, C. krusei, C. albicans, C. glabrata and C. lusitaneae) and Trichosporon asahii, in an in vitro screening. The minimum inhibitory concentrations (MICs) of the active compounds in the screening was determined against 10 clinical isolates of C. parapsilosis and 10 of T. asahii. The compounds 4-pyridin-2-ylbenzaldehyde] (13a) and tert-butyl-(2Z)-2-(3,4,5-trihydroxybenzylidine)hydrazine carboxylate (7b) showed the most promising MIC values in the range of 16-32 μg/mL and 8-16 μg/mL, respectively. The compounds' action on the stability of the cell membrane and cell wall was evaluated, which suggested the action of the compounds on the fungal cell membrane. Cell viability of OPEN ACCESSMolecules 2015, 20 9230 leukocytes and an alkaline comet assay were performed to evaluate the cytotoxicity. Compound 13a was not cytotoxic at the active concentrations. These results support the discovery of promising candidates for the development of new antifungal agents.

Using cycloalkyl and electron-donating groups to decrease the carbonyl electrophilicity, a novel series of 2-(quinoline-4-yloxy)­acetamides was synthesized and evaluated as in vitro inhibitors of Mycobacterium tuberculosis (Mtb) growth. Structure–activity relationship studies led to selective and potent antitubercular agents with minimum inhibitory concentrations in the submicromolar range against drug-sensitive and drug-resistant Mtb strains. An evaluation of the activity of the lead compounds against a spontaneous qcrB mutant strain indicated that the structures targeted the cytochrome bc 1 complex. In addition, selected molecules inhibited Mtb growth in a macrophage model of tuberculosis infection. Furthermore, the leading compound was chemically stable depending on the context and showed good kinetic solubility, high permeability, and a low rate of in vitro metabolism. Finally, the pharmacokinetic profile of the compound was assessed after oral administration to mice. To the best of our knowledge, for the first time, a 2-(quinoline-4-yloxy)­acetamide was obtained with a sufficient exposure, which may enable in vivo effectiveness and its further development as an antituberculosis drug candidate.

We have developed a sequential and selective Pd-catalyzed double-Heck arylation of ethylene that results in non-symmetrical nitro-stilbene analogs of trans-resveratrol at excellent yields. A catalytic system consisting of Pd(OAc) 2 and P(o-tolyl) 3 permitted us to carry out the two consecutive Heck arylations without losing activity from the first to the second Heck reaction. After the first Heck arylation of ethylene, no isolation or additional catalyst loading is required for the second Heck arylation reaction. This protocol was applied to the synthesis of methylated trans-resveratrol, which was obtained at a 65% overall yield. Copyright