RESUMO
Aim: To access the metabolic changes caused by a chalcone derivative (LabMol-75) through a proteomic approach. Methods: Proteomic analysis was performed after 9 h of Paracoccidioides brasiliensis yeast (Pb18) cell incubation with the LabMol-75 at MIC. The proteomic findings were validated through in vitro and in silico assays. Results: Exposure to the compound led to the downregulation of proteins associated with glycolysis and gluconeogenesis, ß-oxidation, the citrate cycle and the electron transport chain. Conclusion: LabMol-75 caused an energetic imbalance in the fungus metabolism and deep oxidative stress. Additionally, the in silico molecular docking approach pointed to this molecule as a putative competitive inhibitor of DHPS.
Assuntos
Paracoccidioides , Paracoccidioidomicose , Paracoccidioides/metabolismo , Proteômica , Simulação de Acoplamento Molecular , Estresse Oxidativo , Oxirredução , Paracoccidioidomicose/microbiologiaRESUMO
Aim: Computer-aided drug design approaches were applied to identify chalcones with antiplasmodial activity. Methodology: The virtual screening was performed as follows: structural standardization of in-house database of chalcones; identification of potential Plasmodium falciparum protein targets for the chalcones; homology modeling of the predicted P. falciparum targets; molecular docking studies; and in vitro experimental validation. Results: Using these models, we prioritized 16 chalcones with potential antiplasmodial activity, for further experimental evaluation. Among them, LabMol-86 and LabMol-87 showed potent in vitro antiplasmodial activity against P. falciparum, while LabMol-63 and LabMol-73 were potent inhibitors of Plasmodium berghei progression into mosquito stages. Conclusion: Our results encourage the exploration of chalcones in hit-to-lead optimization studies for tackling malaria.
Assuntos
Antimaláricos/farmacologia , Chalconas/farmacologia , Desenho Assistido por Computador , Desenho de Fármacos , Malária/tratamento farmacológico , Antimaláricos/uso terapêutico , HumanosRESUMO
AIM: The shape-based virtual screening was used for the identification of new compounds anti-paracoccidioidomycosis (PCM). MATERIALS & METHODS: The study was performed according to the following steps: collection and curation of a dataset of quinolinyl N-oxide chalcones with anti-PCM activity, development and validation of shape-based models, application of the best model for virtual screening, and experimental validation. RESULTS & CONCLUSION: Among 31 computational hits, eight compounds showed potent antifungal activity and low cytotoxicity for mammalian cells. The checkerboard assay showed that most promising hit (compound 3) displayed additive effects with the antifungal cotrimoxazole and amphotericin B. Therefore, the shape-based virtual screening allowed us to discover promising compounds in prospective hit-to-lead optimization studies for tackling PCM.
Assuntos
Antifúngicos/isolamento & purificação , Chalcona/isolamento & purificação , Simulação por Computador , Paracoccidioides/efeitos dos fármacos , Anfotericina B/farmacologia , Animais , Antifúngicos/química , Antifúngicos/farmacologia , Células 3T3 BALB , Chalcona/análogos & derivados , Chalcona/farmacologia , Conjuntos de Dados como Assunto , Desenho de Fármacos , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos/métodos , Eritrócitos/efeitos dos fármacos , Fibroblastos/efeitos dos fármacos , Humanos , Camundongos , Estudos Prospectivos , Combinação Trimetoprima e Sulfametoxazol/farmacologiaRESUMO
Medicinal chemists continue to be fascinated by chalcone derivatives because of their simple chemistry, ease of hydrogen atom manipulation, straightforward synthesis, and a variety of promising biological activities. However, chalcones have still not garnered deserved attention, especially considering their high potential as chemical sources for designing and developing new effective drugs. In this review, we summarize current methodological developments towards the design and synthesis of new chalcone derivatives and state-of-the-art medicinal chemistry strategies (bioisosterism, molecular hybridization, and pro-drug design). We also highlight the applicability of computer-assisted drug design approaches to chalcones and address how this may contribute to optimizing research outputs and lead to more successful and cost-effective drug discovery endeavors. Lastly, we present successful examples of the use of chalcones and suggest possible solutions to existing limitations.
Assuntos
Chalcona , Desenho de Fármacos , Pró-Fármacos , Chalcona/análogos & derivados , Chalcona/síntese química , Chalcona/química , Pró-Fármacos/síntese química , Pró-Fármacos/químicaRESUMO
New anti-tuberculosis (anti-TB) drugs are urgently needed to battle drug-resistant Mycobacterium tuberculosis strains and to shorten the current 6-12-month treatment regimen. In this work, we have continued the efforts to develop chalcone-based anti-TB compounds by using an in silico design and QSAR-driven approach. Initially, we developed SAR rules and binary QSAR models using literature data for targeted design of new heteroaryl chalcone compounds with anti-TB activity. Using these models, we prioritized 33 compounds for synthesis and biological evaluation. As a result, 10 heteroaryl chalcone compounds (4, 8, 9, 11, 13, 17-20, and 23) were found to exhibit nanomolar activity against replicating mycobacteria, low micromolar activity against nonreplicating bacteria, and nanomolar and micromolar against rifampin (RMP) and isoniazid (INH) monoresistant strains (rRMP and rINH) (<1 µM and <10 µM, respectively). The series also show low activity against commensal bacteria and generally show good selectivity toward M. tuberculosis, with very low cytotoxicity against Vero cells (SI = 11-545). Our results suggest that our designed heteroaryl chalcone compounds, due to their high potency and selectivity, are promising anti-TB agents.
Assuntos
Antituberculosos/farmacologia , Chalcona/farmacologia , Descoberta de Drogas , Mycobacterium tuberculosis/efeitos dos fármacos , Relação Quantitativa Estrutura-Atividade , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Animais , Antituberculosos/síntese química , Antituberculosos/química , Chalcona/síntese química , Chalcona/química , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Desenho de Fármacos , Testes de Sensibilidade Microbiana , Estrutura Molecular , Células VeroRESUMO
Leishmaniasis are infectious diseases caused by parasites of genus Leishmania that affect affects 12 million people in 98 countries mainly in Africa, Asia, and Latin America. Effective treatments for this disease are urgently needed. In this study, we present a computer-aided approach to investigate a set of 32 recently synthesized chalcone and chalcone-like compounds to act as antileishmanial agents. As a result, nine most promising compounds and three potentially inactive compounds were experimentally evaluated against Leishmania infantum amastigotes and mammalian cells. Four compounds exhibited EC50 in the range of 6.2-10.98µM. In addition, two compounds, LabMol-65 and LabMol-73, exhibited cytotoxicity in macrophages >50µM that resulted in better selectivity compared to standard drug amphotericin B. These two compounds also demonstrated low cytotoxicity and high selectivity towards Vero cells. The results of target fishing followed by homology modeling and docking studies suggest that these chalcone compounds could act in Leishmania because of their interaction with cysteine proteases, such as procathepsin L. Finally, we have provided structural recommendations for designing new antileishmanial chalcones.