New azoles with potent antifungal activity: Design, synthesis and molecular docking

Che, Xiaoying; Sheng, Chunquan; Wang, Wenya; Cao, Yongbing; Xu, Yulan; Ji, Haitao; Dong, Guoqiang; Miao, Zhenyuan; Yao, Jing; Zhang, Wannian

doi:10.1016/j.ejmech.2009.05.018

Cited by 55 publications

(26 citation statements)

References 29 publications

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“…Che et al developed several azoles and screened them for antimicrobial activity. Compound 114 exhibited maximum antifungal activity with MIC in the range of 0.0156-2 µg/mL when evaluated against different organisms [200]. Amongst the compounds synthesized by Yu et al, compounds 115a and 115b exerted good antifungal activity, when evaluated against Rhizoctonia solani (R. solani).…”

Section: A N U S C R I P Tmentioning

confidence: 98%

Piperazine scaffold: A remarkable tool in generation of diverse pharmacological agents

Shaquiquzzaman

Verma

Marella

et al. 2015

European Journal of Medicinal Chemistry

198

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Section: A N U S C R I P Tmentioning

confidence: 98%

Piperazine scaffold: A remarkable tool in generation of diverse pharmacological agents

Shaquiquzzaman

Verma

Marella

et al. 2015

European Journal of Medicinal Chemistry

198

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“…1,22,23 A fim de minimizar variações experimentais inerentes aos ensaios celulares, utilizou-se a relação CIM80 azol /CIM80 fluconazol , onde o valor de CIM80 azol representa a concentração mínima do derivado azólico necessária para inibir em 80% o crescimento fúngico e o valor de CIM80 fluconazol representa a concentração de fluconazol necessária para produzir o mesmo efeito segundo o protocolo M27-A2 do CLSI (controle do experimento). 24 Os derivados triazólicos tiveram suas coordenadas 3D otimizadas sequencialmente por mecânica molecular, utilizando o campo de força Tripos, e através de cálculos semiempíricos AM1 (palavras chave: 1SCF XYZ ESP NOINTER SCALE=1.4 NSURF=2 SCINCR=0.4), como disponível na plataforma SYBYL-X 1.1.…”

Section: Conjunto De Dadosunclassified

Estudos de QSAR 2D baseados em descritores topológicos e fragmentos moleculares para uma série de derivados azólicos ativos contra Candida albicans

2012

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Recebido em 29/3/11; aceito em 5/9/11; publicado na web em 30/9/11 2D-QSAR STUDIES BASED ON TOPOLOGICAL DESCRIPTORS AND MOLECULAR FRAGMENTS FOR A SERIES OF AZOLE DERIVATIVES ACTIVE AGAINST Candida albicans. Azole derivatives are the main therapeutical resource againstCandida albicans infection in immunocompromised patients. Nevertheless, the widespread use of azoles has led to reduced effectiveness and selection of resistant strains. In order to guide the development of novel antifungal drugs, 2D-QSAR models based on topological descriptors or molecular fragments were developed for a dataset of 74 molecules. The optimal fragment-based model (r 2 = 0.88, q 2 = 0.73 and r 2 pred = 0.62 with 6PCs) and descriptor-based model (r 2 = 0.82, q 2 = 0.79 and r 2 pred = 0.70 with 2 PCs), when analysed synergically, suggested that the triazolone ring and lipophilic properties are both important to antifungal activity.Keywords: antifungal; azole derivatives; QSAR. INTRODUÇÃODurante as últimas duas décadas, o risco de infecções causadas pela levedura patogênica C. albicans tornou-se cada vez mais comum, especialmente em pacientes imunocomprometidos.1-3 Por exemplo, cerca de 90% dos pacientes com HIV têm pelo menos um episódio de candidíase oral, cujo tratamento pode gerar gastos superiores a 55 mil dólares por pessoa. 4,5 Os fármacos de escolha para tratamento dessa infecção pertencem à classe dos derivados azólicos, que exercem sua função biológica através da inibição competitiva da enzima lanosterol 14a desmetilase (CYP51).6 Em função da ampla utilização desses medicamentos, observa-se uma redução na eficácia e aparecimento de cepas resistentes. 7,8 Dentre os principais mecanismos de resistência conhecidos em espécies de Candida estão: superexpressão de bombas de efluxo, diminuindo o acúmulo intracelular do fármaco; alterações na afinidade entre os derivados azólicos e alvo macromolecular, em decorrência de mutações envolvendo o gene ERG11, o qual codifica a enzima lanosterol 14a desmetilase.9-12 Como alternativa para superar esses problemas estão sendo desenvolvidos novos derivados azólicos ativos contra cepas resistentes.Estratégias de planejamento baseado na estrutura do alvo terapêu-tico são amplamente utilizadas pelas grandes indústrias farmacêuticas para identificar moléculas protótipo cuja potência e seletividade devem ser otimizadas através da satisfação de exigências estéreas e eletrônicas presentes apenas no alvo macromolecular.1,13 Entretanto, essa abordagem é limitada pela ausência de informações estruturais da enzima lanosterol 14a-desmetilase de C. albicans.14 A fim de contornar essa restrição, técnicas de modelagem por homologia têm sido empregadas.14,15 Contudo, a baixa identidade sequencial entre as proteínas molde e a proteína alvo, aproximadamente 30%, impede que informações detalhadas sobre a disposição espacial dos resíduos-chave para o reconhecimento molecular sejam identificadas de forma inequívoca. 16 desenvolveram modelos de QSAR 2D, por regressão linear múltipla, que destacam a capacidade de descri...

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“…[1,11,12] respectively were conducted and in these studies speculating design and synthesis of antifungal agents was suggested. However, Che et al [11] designed and synthesized a series of azoles drugs against C. albicans whereas Francis et al [12] modified the structure of 1-benzylamino-2-phenyl-3-(1H-1,2,4-triazol-1-yl)propan-2-ols to act better against C. albicans [11]. Furthermore, Wang et al, designed, synthesized 2-(2,4-Difluorophenyl)-3-(methyl-(3-phenoxyalkyl)amino)-1-(1H-1,2,4-triazol-1-yl)propan-2-ols against C. albicans [1].…”

Section: Introductionmentioning

confidence: 99%

In Silico Analog Design for Terbinafine Against Trichophyton rubrum: A Preliminary Study

2015

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The diseases caused by dermatophytes are common among several other infections which cause serious threat to human health. It is evident that enzyme squalene epoxidase is responsible for prolonged dermatophyte infection and it is appealing to note that this enzyme is also responsible for fatty acid synthesis in these groups of fungi. In the present study, terbinafine drug which targets enzyme squalene epoxidase has been explored to design its various novel analogues. The present study suggests that many more prominent drug analogues could be constituted which may be crucial towards designing new drug candidates. In the present study, we have designed a series of such analogues viz. [(2E)-6,6-dimethylhept-2-en-4-yn-1-yl](methyl)(naphthalen-1-ylmethyl)amine, N-[8-({[(2E)-6,6-dimethylhept-2-en-4-yn-1-yl](methyl)amino}methyl)naphthalen-1-yl]-2-(sulfoamino) acetamide, {[4-(dihydroxyamino)-8-({[(2E)-6,6-dimethylhept-2-en-4-yn-1-yl](methyl)amino}methyl)naphthalen-1-yl]sulfanyl}methanol and (R)-{[4-({[(2E,6R)-6,7-dimethyloct-2-en-4-yn-1-yl](methyl)amino}methyl)-5-[(hydroxysulfamoyl)amino]naphthalen-1-yl]amino}sulfinic acid. Moreover, further by molecular docking approach the binding between enzyme and designed analogues was further analysed. The present preliminary report suggested a considerably good docking interaction score of -338.75 kcal/mol between terbinafine and squalene epoxidase from Trichophyton rubrum. This preliminary study implies that few designed candidate ligands can be effectual towards the activity of this enzyme and can play crucial role in pathogenesis control of T. rubrum.

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New azoles with potent antifungal activity: Design, synthesis and molecular docking

Cited by 55 publications

References 29 publications

Piperazine scaffold: A remarkable tool in generation of diverse pharmacological agents

Piperazine scaffold: A remarkable tool in generation of diverse pharmacological agents

Estudos de QSAR 2D baseados em descritores topológicos e fragmentos moleculares para uma série de derivados azólicos ativos contra Candida albicans

In Silico Analog Design for Terbinafine Against Trichophyton rubrum: A Preliminary Study

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