RESUMO
A series of D-ring fused 16-substituted steroidal quinoxalin-2(1H)-one attached to an electron-releasing (ER) or electron-withdrawing (EW) groups via steroidal oxoacetate intermediate were synthesized to investigate their protein aggregation inhibition potential using human lysozyme (HLZ). The influence of the type of substituent at the C-6 positions of the quinoxalin-2(1H)-one ring on the protein aggregation inhibition potential was observed, showing that the EW moiety improved the protein aggregation inhibition potency. Of all the evaluated compounds, NO2-substituted quinoxalin-2(1H)-one derivative 13 was the most active compound and had a maximum protein aggregation inhibition effect. Significant stabilization effects strongly support the binding of the most biologically active steroidal quinoxalin-2(1H)-one with docking studies. The predicted physicochemical and ADME properties lie within a drug-like space which shows no violation of Lipinski's rule of five except compounds 12 and 13. Combined, our results suggest that D-ring fused 16-substituted steroidal quinoxalin-2(1H)-one has the potential to modulate the protein aggregation inhibition effect.
Assuntos
Simulação de Acoplamento Molecular , Muramidase , Agregados Proteicos , Quinoxalinas , Quinoxalinas/química , Quinoxalinas/farmacologia , Agregados Proteicos/efeitos dos fármacos , Humanos , Muramidase/química , Muramidase/metabolismo , Esteroides/química , Esteroides/farmacologia , Dobramento de ProteínaRESUMO
Working principle of azoles as antifungals is the inhibition of fungal CYP51/lanosterol-14α-demethylase via selective coordination with heme iron. This interaction can also cause side effects by binding to host lanosterol-14α-demethylase. Hence, it is necessary to design, synthesize and test new antifungal agents that have different structures than those of azoles and other antifungal drugs of choice in clinical practice. Consequently, a series of steroidal 1,4-dihydropyridine analogs 16-21 were synthesized and screened for their inâ vitro anti-fungal activity against three Candida species as steroids-based medications have low toxicity, less vulnerability to multi-drug resistance, and high bioavailability by being capable of penetrating the cell wall and binding to specific receptors. Initially, Claisen-Schmidt condensation takes place between steroidal ketone (dehydroepiandrosterone) and an aromatic aldehyde forming steroidal benzylidene 8-13 followed by Hantzsch 1,4-dihydropyridine synthesis resulting in steroidal 1,4-dihydropyridine derivatives 16-21. The results exhibited that compound 17 has significant anti-fungal potential with an MIC value of 750â µg/ml for C.â albicans and C.â glabrata and 800â µg/ml for C.â tropicalis. Inâ silico molecular docking and ADMET studies were also performed for compounds 16-21.
Assuntos
Antifúngicos , Lanosterol , Simulação de Acoplamento Molecular , Lanosterol/farmacologia , Testes de Sensibilidade Microbiana , Antifúngicos/farmacologia , Antifúngicos/química , Azóis/química , Azóis/farmacologia , Candida albicansRESUMO
A series of steroidal thiazolopyrimidine derivatives were developed and evaluated for their antifungal properties against Candida species using steroid as the basic skeletonand a thiazolopyrimidine heterocycle as a pharmacophore in the D-ring. Dehydroepiandrosterone, aromatic aldehydes, and 2-aminothiazole were used in a one-pot multicomponent reaction with silica sulphuric acid to generate the target molecules. Additionally, molecular docking studies were conducted to determine how synthesized steroidal derivatives interacted with the amino acid residues of CYP51 ofCandida albicans.
Assuntos
Antifúngicos , Candida albicans , Antifúngicos/química , Candida , Candida albicans/efeitos dos fármacos , Candida albicans/metabolismo , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Esteroides/química , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologia , Pirimidinas/química , Pirimidinas/farmacologia , Candidíase/tratamento farmacológicoRESUMO
Protein misfolding can lead to fibrillar and non-fibrillar deposits which are the signs of countless human diseases. A promising strategy for the prevention of such diseases is the inhibition of protein aggregation, and the most crucial step toward effective prevention is the development of small molecules having the potential for protein-aggregation inhibition. In this search, a series of novel steroidal pyrido[2,3-d]pyrimidines have been synthesized employing steroidal ketone, substituted aldehydes, and 2,6-diaminopyrimidin-4(3H)-one through the microwave-assisted one-pot multicomponent methodology. The aggregation inhibition potential of newly synthesized compounds was evaluated on human lysozyme (HLZ). All the synthesized compounds were found to be efficient in the inhibition of protein aggregation in carefully designed in vitro experiments. Moreover, molecular docking studies also determine the binding interactions between all the synthesized compounds and native HLZ through hydrogen bonding. The structures of synthesized compounds were also elucidated using various spectroscopic techniques.
Assuntos
Micro-Ondas , Pirimidinas , Humanos , Simulação de Acoplamento Molecular , Agregados Proteicos , Esteroides/química , Desenvolvimento de MedicamentosRESUMO
Steroids are polycyclic compounds and are broadly exist in the natural world and display various biological activities. Many steroidal compounds have been used as traditional medicines, for example, antibacterial and few as hormone like medication. The introduction of heterocycle or heteroatom in the steroidal moiety has a significant biological impact. These derivatives have widespread biological activities such as anticancer, anti-inflammatory, anti-ulcer and antimicrobial. The present article is a brief review of the recent development of synthesis and biological activities of pregnenolone derivatives.