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1.
Chemistry ; 26(19): 4256-4260, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32031278

RESUMO

We report the first chemical synthesis of eurysterol A, a cytotoxic and antifungal marine steroidal sulfate with a unique C8-C19 oxy-bridged cholestane skeleton. After C19 hydroxylation of cholesteryl acetate, used as an inexpensive commercial starting material, the challenging oxidative functionalization of ring B was achieved by two different routes to set up a 5α-hydroxy-7-en-6-one moiety. As a key step, an intramolecular oxa-Michael addition was exploited to close the oxy-bridge (8ß,19-epoxy unit). DFT calculations show this reversible transformation being exergonic by about -30 kJ mol-1 . Along the optimized (scalable) synthetic sequence, the target natural product was obtained in only 11 steps in 5 % overall yield. In addition, an access to (isomeric) 7ß,19-epoxy steroids with a previously unknown pentacyclic ring system was discovered.


Assuntos
Antifúngicos/síntese química , Esteroides/química , Esteróis/síntese química , Antifúngicos/química , Hidroxilação , Isomerismo , Estrutura Molecular , Oxirredução , Esteróis/química
2.
J Mycol Med ; 30(2): 100924, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32037102

RESUMO

Cryptococcus neoformans, an encapsulated fungal pathogen is evolving as a major threat to immune-compromised patients and rarely to healthy individuals also. The cell wall bound capsular polysaccharide, melanin pigment and biofilm formation are major virulence factors that are known to contribute to cryptococcal meningitis. In the present study, a furanone derivative, (E)-5-benzylidenedihydrofuran-2(3H)-one (compound-6) was evaluated against biofilm of seven different strains of C. neoformans in melanized and non-melanized condition. In addition, the efficacy of compound-6 in activation of TLR-2, opsonophagocytosis, and modulation of cytokine expression during phagocytosis were studied. During the biofilm study, we found that moderate capsule size favored biofilm formation. Interestingly, the minimum biofilm eradication concentration (MBEC0.5) of melanized biofilm was found to be achieved at 1- to 1.7-fold higher MBEC0.5 of non-melanized cells. The maximum eradication of 77% and 69% of non-melanized and melanized biofilm were observed. The capsule size was reduced to half of its size with marked changes in morphology. Furthermore, expression of TLR2, iNOS and pro-inflammatory cytokines such as TNF-α, IL-12, and IFN-γ were also facilitated by compound-6. The correlation analysis showed a positive correlation between phagocytosis and the expression of TLR-2, iNOS, IL-6, IL-12. Collectively, the significant effect of compound-6, anti-melanization activity, antibiofilmand effective immunomodulant could be an interesting dual strategy drug agonist against cryptococcal meningitis.


Assuntos
Antifúngicos/farmacologia , Biofilmes/efeitos dos fármacos , Cryptococcus/efeitos dos fármacos , Proteínas Opsonizantes/fisiologia , Fagocitose/efeitos dos fármacos , Animais , Antifúngicos/síntese química , Antifúngicos/química , Cápsulas Bacterianas/efeitos dos fármacos , Cápsulas Bacterianas/fisiologia , Células Cultivadas , Criptococose/imunologia , Criptococose/microbiologia , Cryptococcus/fisiologia , Cryptococcus neoformans/efeitos dos fármacos , Cryptococcus neoformans/fisiologia , Furanos/síntese química , Furanos/química , Furanos/farmacologia , Humanos , Macrófagos/efeitos dos fármacos , Macrófagos/fisiologia , Melaninas/metabolismo , Meningite Criptocócica/imunologia , Meningite Criptocócica/microbiologia , Camundongos , Testes de Sensibilidade Microbiana , Proteínas Opsonizantes/metabolismo
3.
Org Biomol Chem ; 18(7): 1369-1376, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-31996878

RESUMO

This paper discloses a transition metal-free selective C-H dithiocarbamation of drug skeletons using disulfiram (DSF) in the presence of KI/K2S2O8 in DMF/H2O. Drug skeletons, including 5-aminopyrazoles, indoles, pyrroloquinoline, and Julolidine, underwent C-H dithiocarbamation smoothly to afford a variety of drug-like molecules in moderate to good yields. It was found that the in situ formed 5-aminopyrazole iodide is the key intermediate for the dithiocarbamation. Bioassay results show that some of these N-heterocyclic dithiocarbamate derivatives exhibit good antifungal activity against Colletotrichum gloeosprioides and Fusarium oxysporum, F. proliferatum, Fusarium solani, Geotrichum candidum, Penicillium digitatum, Penicillium italicum, Phyricularia grisea.


Assuntos
Antifúngicos/farmacologia , Colletotrichum/efeitos dos fármacos , Fusarium/efeitos dos fármacos , Geotrichum/efeitos dos fármacos , Penicillium/efeitos dos fármacos , Tiocarbamatos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Derivados de Benzeno/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Estereoisomerismo , Tiocarbamatos/síntese química , Tiocarbamatos/química
4.
Chem Commun (Camb) ; 56(12): 1780-1783, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-31938791

RESUMO

Herein, we disclose the first set of unique selenium-containing SnAP reagents for the direct synthesis of C-substituted selenomorpholines and 1,4-selenazepanes, including their amino acid derivatives from commercially available aldehydes under mild conditions. These elusive N-unprotected heterocycles are not accessible by classical routes. Biological evaluation of these compounds revealed promising activities against clinically relevant fungal strains.


Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Candida parapsilosis/efeitos dos fármacos , Compostos de Selênio/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Relação Dose-Resposta a Droga , Testes de Sensibilidade Microbiana , Estrutura Molecular , Compostos de Selênio/síntese química , Compostos de Selênio/química , Relação Estrutura-Atividade
5.
World J Microbiol Biotechnol ; 36(2): 25, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31980951

RESUMO

In a search for novel therapeutic agents against pathogenic fungal species, Candida in addition to bacterial species, novel spinel nanoferrites were assayed against four pathogenic fungi isolated from different clinical samples of ear and skin infections: Aspergillus flavus, A. niger, A. terrus and A. fumigatus, four Candia species: Candida albicans, C. parapsilosis, C. krusei and C. tropicales, and four bacterial species: two Gram +ve: Bacillus subtilis and Streptococcus pyogenes, and two Gram -ve: Pseudomonas vulgaris and Escherichia coli. It was found that the assayed compounds displayed different levels of antifungal and antibacterial activities against all tested microorganisms. The antimicrobial potency depends on the method of synthesis of the nanoparticles and also on the microbial species.


Assuntos
Antibacterianos/síntese química , Antifúngicos/síntese química , Compostos Férricos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Compostos Férricos/química , Compostos Férricos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Nanopartículas , Relação Estrutura-Atividade
6.
J Agric Food Chem ; 68(8): 2306-2315, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-31995378

RESUMO

Neocryptolepine is an alkaloid isolated from traditional African herbal medicine Cryptolepis sanguinolenta, and its broad spectrum of biological activities has been illuminated in past decades. In this study, neocryptolepine and its derivatives (1-49) were designed and synthesized from economical and readily available starting materials. Their structures were confirmed by proton nuclear magnetic resonance, carbon nuclear magnetic resonance, and mass spectrometry. The synthesized compounds were screened for their antifungal profile against six agriculturally important fungi Rhizoctonia solani, Botrytis cinerea (B. cinerea), Fusarium graminearum, Mycosphaerella melonis, Sclerotinia sclerotiorum, and Magnaporthe oryzae. The results of in vitro assay revealed that compounds 5, 21, 24, 35, 40, 45, and 47 presented remarkable antifungal activity against the fungi tested with EC50 values lower than 1 µg/mL. Significantly, compound 24 displayed the most effective inhibitory potency against B. cinerea (EC50 = 0.07 µg/mL), and the data from in vivo experiments revealed that compound 24 demonstrated comparable protective activity with the positive control boscalid. Preliminary mechanism studies indicated that compound 24 showed impressive spore germination inhibitory effectiveness and lower cytotoxicity than azoxystrobin, imparted on normal function of the cell membrane and cell wall, and arrested the normal function of the nucleus. Besides the excellent inhibitory activity against agriculturally important phytopathogenic fungi tested, the designed assemblage possesses several benefits with a high profile of variation in synthesized molecules, the ease of synthesis, and good cost-effectiveness of commercially available synthetic reagents, all of these have highlighted the potential worth of compound 24 as a new and highly efficient agricultural fungicide.


Assuntos
Antifúngicos/farmacologia , Fungicidas Industriais/farmacologia , Doenças das Plantas/microbiologia , Antifúngicos/síntese química , Antifúngicos/química , Botrytis/efeitos dos fármacos , Botrytis/crescimento & desenvolvimento , Fungicidas Industriais/síntese química , Fungicidas Industriais/química , Fusarium/efeitos dos fármacos , Fusarium/crescimento & desenvolvimento , Estrutura Molecular , Rhizoctonia/efeitos dos fármacos , Rhizoctonia/crescimento & desenvolvimento , Relação Estrutura-Atividade
7.
Prep Biochem Biotechnol ; 50(2): 204-214, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31935152

RESUMO

Biotechnology through plant cell cultures in bioreactors is a tool that allows increasing the production of secondary metabolites of commercial interest. The hydrodynamic characterization, in addition to the transfer (OTR) and uptake (OUR) of oxygen through the dynamic method with different aeration rate, were used to see their influence on the production of biomass and saponins. The culture poisoning technique was used to determine the antifungal activity of the SC-2 and SC-3 saponins in vitro. Likewise, the shear or hydrodynamic stress of 273.6 mN/m2 were calculated based on the Reynolds Number. The oxygen supply (OTR) was always greater than the demand (OUR) for all the aeration rate evaluated. Dry weight values of 8.6 gDW/L and a concentration of 2.7 mg/L and 187.3 mg/L of the saponins SC-2 and SC-3 respectively were obtained with an air flow of 0.1 vvm. In addition, it was possible to inhibit the growth of phytopathogenic fungi in vitro by up to 93%, while in vivo it was possible to reduce the infections of strawberry seeds inoculated with phytopathogens, obtaining up to 94% of germinated seeds. This information will facilitate the rational operation of the bioreactor culture system that produces secondary metabolites.


Assuntos
Antifúngicos/síntese química , Reatores Biológicos , Fragaria/microbiologia , Saponinas/síntese química , Saponinas/farmacologia , Solanum/química , Antifúngicos/farmacologia , Linhagem Celular Transformada
8.
Molecules ; 25(2)2020 Jan 12.
Artigo em Inglês | MEDLINE | ID: mdl-31940910

RESUMO

Interest in the synthesis of Bi(III) and Sb(III) dithiocarbamate complexes is on the rise, and this has been attributed to their wide structural diversity and their interesting application as biological agents and in solid state/materials chemistry. The readily available binding sites of the two sulphur atoms within the dithiocarbamate moiety in the complexes confers a wide variety of geometry and interactions that often leads to supramolecular assemblies. Although none of the bismuth or antimony metals are known to play any natural biological function, their dithiocarbamate complexes, however, have proven very useful as antibacterial, antileishmanial, anticancer, and antifungal agents. The dithiocarbamate ligands modulate the associated toxicity of the metals, especially antimony, since bismuth is known to be benign, allowing the metal ion to get to the targeted sites; hence, making it less available for side and other damaging reactions. This review presents a concise chemistry and some known biological potentials of their trivalent dithiocarbamate complexes.


Assuntos
Antimônio/química , Bismuto/química , Complexos de Coordenação/síntese química , Tiocarbamatos/síntese química , Animais , Antibacterianos/síntese química , Antibacterianos/farmacologia , Antifúngicos/síntese química , Antifúngicos/farmacologia , Antimônio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Bismuto/farmacologia , Complexos de Coordenação/farmacologia , Humanos , Modelos Químicos , Tiocarbamatos/farmacologia
9.
Molecules ; 25(2)2020 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-31941142

RESUMO

Reaction of 4-(1-adamantyl)-3-thiosemicarbazide (1) with numerous substituted acetophenones and benzaldehydes yielded the corresponding thiosemicarbazones containing adamantane skeletons. The synthesized compounds were evaluated for their in vitro activities against some Gram-positive and Gram-negative bacteria, and the fungus Candida albicans, and cytotoxicity against four cancer cell lines (Hep3B, HeLa, A549, and MCF-7). All of them showed good antifungal activity against Candida albicans. Compounds 2c, 2d, 2g, 2j and 3a, 3e, 3g displayed significant inhibitory activity against Enterococcus faecalis. Compounds 2a, 2e, 2h, 2k and 3j had moderate inhibitory potency against Staphylococcus aureus. Compounds 2a, 2e and 2g found so good inhibitory effect on Bacillus cereus. Compounds 2d and 2h, which contain (ortho) hydroxyl groups on the phenyl ring, were shown to be good candidates as potential agents for killing the tested cancer cell lines, i.e., Hep3B, A549, and MCF-7. Compounds 2a-c, 2f, 2g, 2j, 2k, 3g, and 3i were moderate inhibitors against MCF-7.


Assuntos
Adamantano/química , Antibacterianos , Antifúngicos , Antineoplásicos , Bactérias/crescimento & desenvolvimento , Candida albicans/crescimento & desenvolvimento , Neoplasias , Tiossemicarbazonas , Células A549 , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Antifúngicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Células HeLa , Humanos , Células MCF-7 , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Tiossemicarbazonas/síntese química , Tiossemicarbazonas/química , Tiossemicarbazonas/farmacologia
10.
Chem Biodivers ; 17(1): e1900462, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31788939

RESUMO

A series of coumarin-tagged ß-lactam triazole hybrids (10a-10o) were synthesized and tested for their cytotoxic activity against MDA-MB-231 (triple negative breast cancer), MCF-7 (estrogen receptor positive breast cancer (ER+)) and A549 (human lung carcinoma) cancer cell lines including one normal cell line, HEK-293 (human embryonic kidney). Two compounds 10b and 10d exhibited substantial cytotoxic effect against MCF-7 cancer cell lines with IC50 values of 53.55 and 58.62 µm, respectively. More importantly, compounds 10b and 10d were non-cytotoxic against HEK-293 cell lines. Structure-activity relationship (SAR) studies suggested that the nitro and chloro group at the C-3 position of phenyl ring are favorable for anticancer activity, particularly against MCF-7 cell lines. Furthermore, antimicrobial evaluation of these compounds revealed modest inhibition of examined pathogenic strains with compounds 10c and 10i being the most promising antimicrobial agents against Pseudomonas aeruginosa and Candida albicans, respectively.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Cumarínicos/farmacologia , Triazóis/farmacologia , beta-Lactamas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Proliferação de Células/efeitos dos fármacos , Cumarínicos/síntese química , Cumarínicos/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Células MCF-7 , Testes de Sensibilidade Microbiana , Estrutura Molecular , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/crescimento & desenvolvimento , Relação Estrutura-Atividade , Triazóis/química , beta-Lactamas/química
11.
Chem Biodivers ; 17(2): e1900570, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31778280

RESUMO

A series of sarisan analogs containing 1,3,4-oxadiazole moieties were synthesized by iodine-mediated oxidative cyclization and screened in vitro for their antifungal activities at 50 µg/mL against five phytopathogenic fungi such as Valsa mali, Curvularia lunata, Alternaria alternate, Fusarium solani and Fusarium graminearum. 1,3,4-Oxadiazole derivatives 7e, 7p, 7r, 7t and 7u exhibited potent and a broad spectrum of antifungal activities against at least three phytopathogenic fungi at the concentration of 50 µg/mL. Especially, compound 7r displayed more potent antifungal activities against five phytopathogenic fungi than the positive control hymexazol. The EC50 of 7r against V. mali, C. lunata and A. alternate were 12.6, 14.5 and 17.0 µg/mL, respectively. Additionally, some interesting results of structure-activity relationships (SARs) were also observed.


Assuntos
Antifúngicos/síntese química , Produtos Biológicos/síntese química , Dioxolanos/química , Desenho de Fármacos , Oxidiazóis/química , Alternaria/efeitos dos fármacos , Antifúngicos/farmacologia , Ascomicetos/efeitos dos fármacos , Produtos Biológicos/farmacologia , Dioxolanos/farmacologia , Fusarium/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade
12.
J Appl Microbiol ; 128(2): 438-457, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31650655

RESUMO

AIMS: Investigate the capability of Aspergillus brasiliensis ATCC 16404 to mycosynthesize Co3 O4 -NPs. METHODS AND RESULTS: Mycelial cell-free filtrate of A. brasiliensis ATCC 16404 was applied for mycosynthesis of Co3 O4 -NPs. The preliminary indication for the formation of Co3 O4 -NPs was the change in colour from yellow to reddish-brown. One-factor-at a time-optimization technique was applied to determine the optimum physicochemical conditions required for the mycosynthesis of Co3 O4 -NPs and they were found to be: 72 h for reaction time, pH 11, 30°C, 100 rev min-1 for shaking speed in the darkness using 4 mmol l-1 of CoSO4. 7H2 O and 5·5% of A. brasiliensis dry weight mycelium (w/v). The mycosynthesized Co3 O4 -NPs were characterized using various techniques: spectroscopy including UV/Vis spectrophotometry, dynamic light scattering (DLS), zeta potential measurement, energy-dispersive X-ray analysis, Fourier transform infrared spectroscopy and X-ray diffraction; and vibrating sample magnetometry and microscopy including field emission scanning electron microscopy and high-resolution transmission electron microscopy. Spectroscopic techniques confirmed the formation of Co3 O4 -NPs and the microscopic ones confirmed the shape and size of the mycosynthesized Co3 O4 -NPs as quasi-spherical shaped, monodispersed nanoparticles with a nano size range of 20-27 nm. The mycosynthesized Co3 O4 -NPs have excellent magnetic properties and exhibited a good antimicrobial activity against some pathogenic micro-organisms. CONCLUSION: Ferromagnetic Co3 O4 -NPs with considerable antimicrobial activity were for the first time mycosynthesized. SIGNIFICANCE AND IMPACT OF THE STUDY: The use of fungi as potential bionanofactories for mycosynthesis of nanoparticles is relatively a recent field of research with considerable prospects.


Assuntos
Antifúngicos/química , Antifúngicos/farmacologia , Aspergillus/efeitos dos fármacos , Cobalto/química , Cobalto/farmacologia , Nanopartículas Metálicas/química , Nanopartículas Metálicas/toxicidade , Óxidos/química , Óxidos/farmacologia , Antifúngicos/síntese química , Aspergillus/crescimento & desenvolvimento , Magnetismo , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Espectroscopia de Infravermelho com Transformada de Fourier , Difração de Raios X
13.
Chem Pharm Bull (Tokyo) ; 68(1): 64-69, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31708557

RESUMO

Invasive fungal disease constitutes a growing health problem and development of novel antifungal drugs with high potency and selectivity are in an urgent need. In this study, a novel series of triazole derivatives containing different ester skeleton were designed and synthesized. Microdilution broth method was used to investigate antifungal activity. Significant inhibitory activity of compounds 5c, 5d, 5e, 5f, 5m and 5n was evaluated against the Candida albicans (I), Candida albicans clinical isolate (II), Candida glabrata clinical isolate (I), and Candida glabrata (II) with minimum inhibitory concentrations (MIC80) values ranging from 2 to 16 µg/mL. Notably, compounds 5e and 5n showed the best inhibition against Candida albicans (II), Candida glabrata (I), and Candida glabrata (II) at the concentrations of 2 and 8 µg/mL, respectively. Molecular docking study revealed that the target compounds interacted with CYP51 mainly through hydrophobic and van der Waals interactions. The results indicated that these novel triazole derivatives could serve as promising leads for development of antifungal agents.


Assuntos
Antifúngicos/síntese química , Desenho de Fármacos , Simulação de Acoplamento Molecular , Triazóis/química , Antifúngicos/química , Antifúngicos/farmacologia , Sítios de Ligação , Candida/efeitos dos fármacos , Domínio Catalítico , Ésteres/química , Testes de Sensibilidade Microbiana , Eletricidade Estática , Esterol 14-Desmetilase/química , Esterol 14-Desmetilase/metabolismo , Relação Estrutura-Atividade , Triazóis/síntese química , Triazóis/farmacologia
14.
Med Chem ; 16(1): 104-118, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30398118

RESUMO

OBJECTIVE: Due to the incidence of resistance, a series of sulfonamide-derived 1,2,4- triazoles were synthesized and evaluated. METHOD: The novel sulfonamide-derived 1,2,4-triazoles were prepared starting from commercial acetaniline and chlorosulfonic acid by sulfonylation, aminolysis, N-alkylation and so on. The antimicrobial activity of the synthesized compounds were evaluated in vitro by two-fold serial dilution technique. RESULTS: In vitro antimicrobial evaluation found that 2-chlorobenzyl sulfonamide 1,2,4-triazole 7c exhibited excellent antibacterial activities against MRSA, B. subtilis, B. typhi and E. coli with MIC values of 0.02-0.16 µmol/mL, which were comparable or even better than Chloromycin. The preliminary mechanism suggested that compound 7c could effectively bind with DNA, and also it could bind with human microsomal heme through hydrogen bonds in molecular docking. Computational chemical studies were performed on compound 7c to understand the structural features that are essential for activity. Additionally, compound 7c could generate a small amount of reactive oxygen species (ROS). CONCLUSION: Compound 7c could serve as a potential clinical antimicrobial candidate.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Sulfonamidas/farmacologia , Triazóis/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Bacillus/efeitos dos fármacos , Relação Dose-Resposta a Droga , Desenho de Fármacos , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Saccharomyces cerevisiae/efeitos dos fármacos , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Triazóis/síntese química , Triazóis/química
15.
Med Chem ; 16(1): 128-139, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-30501601

RESUMO

BACKGROUND: It is assumed that the unfavorable selective toxicity of an antifungal drug Amphotericin B (AmB) can be improved upon chemical modification of the antibiotic molecule. OBJECTIVE: The aim of this study was verification of the hypothesis that introduction of bulky substituents at the amino sugar moiety of the antibiotic may result in diminishment of mammalian in vitro toxicity of thus prepared AmB derivatives. METHODS: Twenty-eight derivatives of AmB were obtained upon chemical modification of the amino group of mycosamine residue. This set comprised 10 N-succinimidyl-, 4 N-benzyl-, 5 Nthioureidyl- and 9 N-aminoacyl derivatives. Parameters characterizing biological in vitro activity of novel compounds were determined. RESULTS: All the novel compounds demonstrated lower than AmB antifungal in vitro activity but most of them exhibited negligible cytotoxicity against human erythrocytes and three mammalian cell lines. In consequence, the selective toxicity of majority of novel antifungals, reflected by the selective toxicity index (STI = EH50/IC50) was improved in comparison with that of AmB, especially in the case of 5 compounds. The novel AmB derivatives with the highest STI, induced substantial potassium efflux from Candida albicans cells at concentrations slightly lower than IC50s but did not trigger potassium release from human erythrocytes at concentrations lower than 100 µg/mL. CONCLUSION: Some of the novel AmB derivatives can be considered promising antifungal drug candidates.


Assuntos
Anfotericina B/farmacologia , Antifúngicos/farmacologia , Hexosaminas/farmacologia , Anfotericina B/síntese química , Anfotericina B/química , Antifúngicos/síntese química , Antifúngicos/química , Aspergillus/efeitos dos fármacos , Candida/efeitos dos fármacos , Cryptococcus/efeitos dos fármacos , Relação Dose-Resposta a Droga , Fusarium/efeitos dos fármacos , Hexosaminas/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Mucor/efeitos dos fármacos , Rhizopus/efeitos dos fármacos , Relação Estrutura-Atividade
16.
Chem Biodivers ; 17(2): e1900624, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31863703

RESUMO

In search for new fungicidal and free radical scavenging agents, we synthesized a focused library of 2-chloroquinoline based monocarbonyl analogs of curcumin (MACs). The synthesized MACs were evaluated for in vitro antifungal and antioxidant activity. The antifungal activity was evaluated against five different fungal strains such as Candida albicans, Fusarium oxysporum, Aspergillus flavus, Aspergillus niger, and Cryptococcus neoformans, respectively. Most of the synthesized MACs displayed promising antifungal activity compared to the standard drug Miconazole. Furthermore, molecular docking study on a crucial fungal enzyme sterol 14α-demethylase (CYP51) could provide insight into the plausible mechanism of antifungal activity. MACs were also screened for in vitro radical scavenging activity using butylated hydroxytoluene (BHT) as a standard. Almost all MACs exhibited better antioxidant activity compared to BHT.


Assuntos
Antifúngicos/síntese química , Antioxidantes/química , Curcumina/análogos & derivados , Proteínas Fúngicas/metabolismo , Simulação de Acoplamento Molecular , Quinolinas/química , Antifúngicos/metabolismo , Antifúngicos/farmacologia , Aspergillus/efeitos dos fármacos , Sítios de Ligação , Candida albicans/efeitos dos fármacos , Domínio Catalítico , Cryptococcus neoformans/efeitos dos fármacos , Curcumina/metabolismo , Curcumina/farmacologia , Proteínas Fúngicas/química , Testes de Sensibilidade Microbiana , Esterol 14-Desmetilase/química , Esterol 14-Desmetilase/metabolismo
17.
Chem Pharm Bull (Tokyo) ; 67(12): 1314-1323, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31787658

RESUMO

Condensation of rhodanine (1) with pyrazol-3(2H)-one derivatives (2a-f) gave 5-substituted-2-thioxo-1,3-thiazolidin-4-one derivatives (3a-f). Reaction of compound (1) with 2-arylmethylidene-malononitrile (4a-d) yielded the unexpected derivatives (5a-d). The latter compounds were subjected to cyclization reactions with malononitrile under different basic conditions, hydroxylamine hydrochloride and/or thiourea to furnish the fused thiazole derivatives (6a-d) and (8-10a-d). Coupling of (1) with diazotized aromatic amines (11a-c) in pyridine afforded the arylhydrazones (12a-c). Fusion of latter compounds with malononitrile afforded the thiazolopyridazine derivatives (13a-c). The structures of the newly synthesized compounds were elucidated via spectral data and elemental analyses. The in-vitro cytotoxic activity of compounds (3a-f) against the cell line MCF-7 was evaluated. Also, the synthesized products were investigated for their antibacterial and antifungal activities against six standard organisms including the G+ bacteria, Staphylococcus aureus and Bacillus subtilis, G- bacteria, Escherichia coli and Proteus vulgaris in addition to fungi, Candida albicans and Aspergillus flavus.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Compostos Heterocíclicos/farmacologia , Tiazóis/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Aspergillus flavus/efeitos dos fármacos , Bacillus subtilis/efeitos dos fármacos , Candida albicans/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Escherichia coli/efeitos dos fármacos , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Humanos , Células MCF-7 , Testes de Sensibilidade Microbiana , Proteus vulgaris/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Tiazóis/química
20.
Molecules ; 25(1)2019 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-31877731

RESUMO

There is a continuous search for more reliable and effective alternatives to control phytopathogens through different strategies. In this context, indole-containing phytoalexins are stimuli-induced compounds implicated in plant defense against plant pathogens. However, phytoalexins' efficacy have been limited by fungal detoxifying mechanisms, thus, the research on bioisosteres-based analogs can be a friendly alternative regarding the control of Fusarium phytopathogens, but there are currently few studies on it. Thus, as part of our research on antifungal agents, a set of 21 synthetic indole-containing phytoalexin analogs were evaluated as inhibitors against the phyopathogen Fusarium oxysporum. Results indicated that analogs of the N,N-dialkylthiourea, N,S-dialkyldithiocarbamate and substituted-1,3-thiazolidin-5-one groups exhibited the best docking scores and interaction profiles within the active site of Fusarium spp. enzymes. Vina scores exhibited correlation with experimental mycelial growth inhibition using supervised statistics, and this antifungal dataset correlated with molecular interaction fields after CoMFA. Compound 24 (tert-butyl (((3-oxo-1,3-diphenylpropyl)thio)carbonothioyl)-l-tryptophanate), a very active analog against F. oxysporum, exhibited the best interaction with lanosterol 14α-demethylase according to molecular docking, molecular dynamics and molecular mechanic/poisson-boltzmann surface area (MM/PBSA) binding energy performance. After data analyses, information on mycelial growth inhibitors, structural requirements and putative enzyme targets may be used in further antifungal development based on phytoalexin analogs for controlling phytopathogens.


Assuntos
Antifúngicos/síntese química , Fusarium/crescimento & desenvolvimento , Indóis/síntese química , Sesquiterpenos/química , Antifúngicos/química , Antifúngicos/farmacologia , Domínio Catalítico/efeitos dos fármacos , Simulação por Computador , Enzimas/química , Enzimas/farmacologia , Proteínas Fúngicas/química , Proteínas Fúngicas/farmacologia , Fusarium/efeitos dos fármacos , Fusarium/enzimologia , Indóis/química , Indóis/farmacologia , Viabilidade Microbiana/efeitos dos fármacos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular
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