RESUMO
Type 2 diabetes mellitus (T2DM) is one of the most widely prevalent metabolic disorders with no cure to date thus remains the most challenging task in the current drug discovery. Therefore, the only strategy to control diabetes prevalence is to develop novel efficacious therapeutics. Dipeptidyl Peptidase 4 (DPP-4) inhibitors are currently used as anti-diabetic drugs for the inhibition of incretins. This study aims to construct the chemical feature based on pharmacophore models for dipeptidyl peptidase IV. The structure-based pharmacophore modeling has been employed to evaluate new inhibitors of DPP-4. A four-featured pharmacophore model was developed from crystal structure of DPP-4 enzyme with 4-(2-aminoethyl) benzenesulfonyl fluoride in its active site via pharmacophore constructing tool of Molecular Operating Environment (MOE) consisting F1 Hyd (hydrophobic region), F2 Hyd|Cat|Don (hydrophobic cationic and donor region), F3 Acc (acceptor region) and F4 Hyd (hydrophobic region). The generated pharmacophore model was used for virtual screening of in-house compound library (the available compounds which were used for initial screening to get the few compounds for the current studies). The resultant selected compounds, after virtual screening were further validated using in vitro assay. Furthermore, structure-activity relationship was carried out for the compounds possessing significant inhibition potential after docking studies. The binding free energy of analogs was evaluated via molecular mechanics generalized Born surface area (MM-GBSA) and Poisson-Boltzmann surface area (MM-PBSA) methods using AMBER 16 as a molecular dynamics (MD) simulation package. Based on potential findings, we report that selected candidates are more likely to be used as DPP-4 inhibitors or as starting leads for the development of novel and potent DPP-4 inhibitors.
Assuntos
Dipeptidil Peptidase 4/efeitos dos fármacos , Inibidores da Dipeptidil Peptidase IV/farmacologia , Hipoglicemiantes/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/química , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/uso terapêutico , Técnicas In Vitro , Simulação de Dinâmica Molecular , Relação Estrutura-AtividadeRESUMO
The present paper reports an easy preparation of imines of N-methyl-1H-indole-3-carboxaldehyde by its condensation with alkyl and aromatic amines in ethanol without using any catalyst or dehydrating agent. The compounds have been screened for their antibacterial, antifungal, crown gall tumor inhibitory, and cytotoxic activities. As a major finding some of the compounds exhibited potential biological activity. The imine containing a 4-chlorophenyl group exhibits potential antitumor activity and brine shrimp lethality against crown gall tumor and brine shrimps, respectively. Furthermore, this imine containing a 4-chlorophenyl group also exhibits significant antifungal activity against Candida albicans fungal strains. The compound containing N-diphenylmethyl group has been observed most active against the Gram-positive bacteria.
Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antineoplásicos/farmacologia , Indóis/farmacologia , Tumores de Planta , Agrobacterium tumefaciens/patogenicidade , Animais , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Antineoplásicos/síntese química , Antineoplásicos/química , Artemia/efeitos dos fármacos , Bactérias/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Fungos/efeitos dos fármacos , Humanos , Indóis/síntese química , Indóis/química , Testes de Sensibilidade Microbiana , Conformação Molecular , Estrutura Molecular , Tumores de Planta/microbiologia , Solanum tuberosum/microbiologia , Relação Estrutura-AtividadeRESUMO
The paper describes the synthesis and antimicrobial (antileishmanial, antibacterial and antifungal) activity of some classical hydrazones of benzophenones and of 1,2-diketones. N-(Diaryl) acyl derivatives of these hydrazones have also been synthesized and evaluated. 4,4,-Demthoxybenzil monohydrazone and 4,4'-dimethoxybenzophenone hydrazone showed significant antileishmanial activity. The effect of substituents on the bioactivity is discussed.
Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Antiprotozoários/farmacologia , Hidrazonas/farmacologia , Cetonas/farmacologia , Antibacterianos/síntese química , Antifúngicos/síntese química , Antiprotozoários/síntese química , Bacillus subtilis/efeitos dos fármacos , Bacillus subtilis/crescimento & desenvolvimento , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Escherichia coli/efeitos dos fármacos , Escherichia coli/crescimento & desenvolvimento , Fusarium/efeitos dos fármacos , Fusarium/crescimento & desenvolvimento , Hidrazonas/síntese química , Cetonas/síntese química , Klebsiella pneumoniae/efeitos dos fármacos , Klebsiella pneumoniae/crescimento & desenvolvimento , Leishmania major/efeitos dos fármacos , Leishmania major/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Microsporum/efeitos dos fármacos , Microsporum/crescimento & desenvolvimento , Estrutura Molecular , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Relação Estrutura-AtividadeRESUMO
A series of N-(1-methyl-1H-indol-3-yl)methyleneamines and eight new 3,3-diaryl-4-(1-methyl-1H-indol-3-yl)azetidin-2-ones have been synthesized and screened for their antileishmanial activity against Leishmania major. 3,3-Diaryl-4-(1-methyl-1H-indol-3-yl)azetidin-2-ones have been synthesized by the Staudinger's ketene-imine cycloaddition employing two 2-diazo-1,2-diarylethanones as the precursors of diarylketenes. A marked improvement in anti-parasitic activity is observed by transformation of the methyleneamines to azetidin-2-ones in seven out of eight compounds. Two compounds displayed antileishmanial activity comparable to that of the clinically used antileshmanial drug, amphotericine B.
Assuntos
Antiprotozoários/química , Antiprotozoários/farmacologia , Azetidinas/química , Azetidinas/farmacologia , Indóis/química , Indóis/farmacologia , Leishmania major/efeitos dos fármacos , Antiprotozoários/síntese química , Azetidinas/síntese química , Humanos , Indóis/síntese química , Leishmaniose Cutânea/tratamento farmacológico , Relação Estrutura-AtividadeRESUMO
A series of eighteen azomethines has been synthesized by the reaction of appropriate primary aromatic amines with aryl and/or heteroaryl carboxaldehydes. The synthesized azomethines have been evaluated for their in vitro antileishmanial, antibacterial and antifungal activities. The results revealed some antifungal activity of most of the synthesized compounds, whereas the antileishmaniasis activity results highlighted that all synthesized azomethines inhibited parasite growth and most of them showed highly potent action towards Leishmania major promastigotes. No remarkable bactericidal activities were observed.