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1.
Molecules ; 26(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800731

RESUMO

The preparation of a new non-natural gabosine is reported, in which the chirality is transferred from the toluene's biotransformed metabolite (1R,2S)-3-methylcyclohexa-3.5-diene-1,2-diol. Further chemical transformations to introduce additional functionality and chirality to the molecule were also accomplished.


Assuntos
Cicloexanonas/síntese química , Catálise , Estrutura Molecular , Estereoisomerismo
2.
Saudi Pharm J ; 27(8): 1064-1074, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31885466

RESUMO

Development of new antimicrobial agents, capable of combating resistant and multidrug-resistant fungal and bacterial clinical strains, is necessary. This study presents the synthesis and antimicrobial screening of 42 2-substituted-1,4-benzenediols, being 10 novel compounds. In total, 23 compounds showed activity against fungi and/or bacteria. Benzenediol compounds 2, 5, 6, 8, 11, and 12 demonstrated broad spectrum antimicrobial actions, including resistant and multidrug-resistant species of dermatophytes (Trichophyton mentagrophytes), Candida spp. and the ESKAPE panel of bacteria. Minimum inhibitory concentrations of these compounds for fungi and bacterial strains ranged from 25 to 50 µg/ml and 8-128 µg/ml, respectively. The antifungal mechanism of action is related to the fungal cell wall of dermatophytes and membrane disruption to dermatophytes and yeasts, in the presence of compound 8. Specific structural changes, such as widespread thinning along the hyphae and yeast lysis, were observed by scanning electron microscopy. The effects of compound 8 on cell viability are dose-dependent; however they did not cause genotoxicity and mutagenicity in human leukocyte cells nor haemolysis. Moreover, the compounds were identified as nonirritant by the ex-vivo Hen's egg test-chorioallantoic membrane (HET-CAM). The furan-1,4-benzenediol compound 5 showed in vivo efficacy to combat S. aureus infection using embryonated chicken eggs. Therefore, the compounds 8, and 5 are promising as hits for the development of new antimicrobial drugs with reduced toxicity.

3.
Acta Crystallogr E Crystallogr Commun ; 75(Pt 9): 1362-1366, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31523467

RESUMO

Lapachol acetate [systematic name: 3-(3-methyl-but-2-en-yl)-1,4-dioxonaph-thalen-2-yl acetate], C17H16O4, was prepared using a modified high-yield procedure and its crystal structure is reported for the first time 80 years after its first synthesis. The full spectroscopic characterization of the mol-ecule is reported. The mol-ecular conformation shows little difference with other lapachol derivatives and lapachol itself. The packing is directed by inter-molecular π-π and C-H⋯O inter-actions, as described by Hirshfeld surface analysis. The former inter-actions make the largest contributions to the total packing energy in a ratio of 2:1 with respect to the latter.

4.
J Infect Dev Ctries ; 13(6): 565-576, 2019 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-32058992

RESUMO

INTRODUCTION: Chagas disease and Leishmaniasis are among the most important parasitic diseases. They are considered to be within the most relevant group of neglected tropical diseases and have been included as priorities for searching new drugs due to their several treatment limitations. These parasitic diseases caused by flagellated protozoans affect more than 20 million people predominantly in developing countries. METHODOLOGY: In this study, we prepared a series of 2-substituted 1,4-benzenediols by an efficient, green, and lithium salt-free synthesis in water/ethanol as solvent to test their anti-parasitic activity. All 36 phenolic derivatives were evaluated in vitro for their activity against T. cruzi epimastigotes, L. infantum, and L. braziliensis promastigotes, as well as their cytotoxicity on macrophage and fibroblast cell lines. RESULTS: Based on the results obtained, the compounds that presented a methyl, trifluoromethyl or bromo group at the para-position of the second benzene ring were found the most active analogs, with higher selective index values on the three parasites assayed. CONCLUSION: This evidence suggests that the anti-parasitic activity observed in these analogs is affected by the size of the group at the 4-position of the second ring, but not related with electronic factors.This study identified hit compounds with the potential to target several kinetoplastid parasites.


Assuntos
Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Hidroquinonas/síntese química , Hidroquinonas/farmacologia , Leishmania braziliensis/efeitos dos fármacos , Leishmania infantum/efeitos dos fármacos , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antiprotozoários/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Humanos , Hidroquinonas/toxicidade , Macrófagos/efeitos dos fármacos , Camundongos , Testes de Sensibilidade Parasitária , Relação Estrutura-Atividade
5.
Molecules ; 23(7)2018 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-29986401

RESUMO

An efficient and facile general method for the synthesis of conduritol C analogs, taking advantage of an enantioselective biocatalysis process of monosubstituted benzenes, is described. The absolute stereochemical patterns of the target molecules (−)-conduritol C, (−)-bromo-conduritol C, and (−)-methyl-conduritol C were achieved by means of chemoenzymatic methods. The stereochemistry present at the homochiral cyclohexadiene-cis-1,2-diols derived from the arene biotransformation and the enantioselective ring opening of a non-isolated vinylepoxide derivative permitted the absolute configuration of the carbon bearing the hydroxyl groups at the target molecules to be established. All three conduritols and two intermediates were crystallized, and their structures were confirmed by X-ray diffraction. The three conduritols and intermediates were isostructural. The versatility of our methodology is noteworthy to expand the preparation of conduritol C analogs starting from toluene dioxygenase (TDO) monosubstituted arene substrates.


Assuntos
Cicloexanóis/síntese química , Cicloexenos/síntese química , Biocatálise , Biotransformação , Cristalografia por Raios X , Cicloexanóis/química , Cicloexenos/química , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo
6.
Acta Crystallogr E Crystallogr Commun ; 73(Pt 4): 606-609, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-28435731

RESUMO

The mol-ecule of the title keto carbasugar, C7H10O4, is formed by a cyclo-hexene skeleton with an envelope conformation, substituted by carbonyl, methyl and hydroxyl groups. The crystal structure is controlled mainly by a combination of strong O-H⋯O and weak C-H⋯O hydrogen bonds, forming nearly perpendicular chains running parallel to the [110] and [-110] directions. This perpendicularity is caused by a tetra-gonal pseudosymmetry influenced by the similarity between the a and b axes, the value of 90.9770 (10)° of the ß angle and the action of a 21 screw axis, which transform each chain into its corresponding nearly orthogonal one.

7.
Acta Crystallogr E Crystallogr Commun ; 73(Pt 1): 81-84, 2017 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-28083142

RESUMO

The absolute configuration, i.e. (3aR,3'aR,7aS,7'aS), of the title compound, C18H26O4, synthesized via a palladium-catalyzed homocoupling reaction, was determined on the basis of the synthetic pathway and was confirmed by X-ray diffraction. The homocoupled mol-ecule is formed by two chemically identical moieties built up from two five- and six-membered fused rings. The supra-molecular assembly is controlled mainly by C-H⋯O inter-actions that lead to the formation of hydrogen-bonded chains of mol-ecules along the [001] direction, while weak dipolar inter-actions and van der Waals forces hold the chains together in the crystal structure.

8.
Acta Crystallogr E Crystallogr Commun ; 71(Pt 9): 1013-6, 2015 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-26396837

RESUMO

The absolute configuration of the title compound, C10H16O4, determined as 3aS,4S,5R,7aR on the basis of the synthetic pathway, was confirmed by X-ray diffraction. The mol-ecule contains a five- and a six-membered ring that adopt twisted and envelope conformations, respectively. The dihedral angle between the mean planes of the rings is 76.80 (11)° as a result of their cis-fusion. In the crystal, mol-ecules are linked by two pairs of O-H⋯O hydrogen bonds, forming chains along [010]. These chains are further connected by weaker C-H⋯O inter-actions along [100], creating (001) sheets that inter-act only by weak van der Waals forces.

9.
Parasitol Int ; 64(5): 295-8, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25843766

RESUMO

In this study, we report the in vivo efficacy of 14-hydroxylunularin evaluated in BALB/c mice experimentally infected with promastigotes of Leishmania infantum (syn L. chagasi), the major causative agent of visceral leishmaniasis in Latin America. Seven days post-infection, treatment with 14-hydroxylunularin started and it was administered by oral and subcutaneous routes in doses of 10 and 25 mg/kg of weight for ten days using Glucantime® as reference drug. In the liver, the evaluated compound showed parasite reduction above 90% by both administration routes being the oral route the most effective at both doses. Significant decreased numbers of parasites were also observed when the treated group was compared with the control group (p≤0.05). The subcutaneous route presented a remarkable difference with at least 80% parasite suppression in liver and spleen at 10 mg/kg dose and 90% in liver at 25 mg/kg. The leishmanicidal activity of 14-hydroxylunularin against L. infantum revealed by this study is another evidence in favor of this compound as a potential candidate for the development of a new oral treatment for leishmaniasis.


Assuntos
Anti-Helmínticos/farmacologia , Bibenzilas/farmacologia , Leishmania infantum/efeitos dos fármacos , Leishmaniose Visceral/tratamento farmacológico , Fenóis/farmacologia , Animais , Modelos Animais de Doenças , Leishmaniose Visceral/parasitologia , Fígado/parasitologia , Masculino , Meglumina/farmacologia , Antimoniato de Meglumina , Camundongos , Camundongos Endogâmicos BALB C , Compostos Organometálicos/farmacologia , Baço/parasitologia
10.
Eur J Med Chem ; 43(9): 1797-807, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18192088

RESUMO

The synthesis and potent antiprotozoal activity of 14-hydroxylunularin, a natural hydroxybibenzyl bryophyte constituent is reported. 14-hydroxylunularin was highly active in vitro assays against culture and intracellular forms of Leishmania spp. and Trypanosoma. cruzi, in absence of cytotoxicity against mammalian cells. Preliminary structure-activity relationship studies showed that the reported bioactivity depends on hybridization at the carbon-carbon bridge, position and number of free hydroxy group on the aromatic rings. The reported results were also in agreement with the in silico prediction using Non-Stochastic Quadratic Fingerprints-based algorithms. The same compound also showed antiprotozoal activity in Leishmania spp. infected mice by oral and subcutaneous administration routes, with an optimal treatment of a daily subcutaneous administration of 10 mg/kg of body weight for 15 days. This study suggested that 14-hydroxylunularin may be chosen as a new candidate in the development of leishmanicidal therapy.


Assuntos
Antiprotozoários/farmacologia , Antiprotozoários/uso terapêutico , Bibenzilas/farmacologia , Biologia Computacional , Leishmania/efeitos dos fármacos , Fenóis/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Animais , Antiprotozoários/química , Bibenzilas/química , Bibenzilas/uso terapêutico , Bovinos , Linhagem Celular , Espaço Extracelular/efeitos dos fármacos , Feminino , Concentração Inibidora 50 , Espaço Intracelular/efeitos dos fármacos , Leishmania/citologia , Leishmaniose/tratamento farmacológico , Masculino , Camundongos , Fenóis/química , Fenóis/uso terapêutico
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