RESUMO
Human immunodeficiency virus type 1 (HIV-1) is a public health problem that affects over 38 million people worldwide. Although there are highly active antiretroviral therapies, emergence of antiviral resistant strains is a problem which leads to almost a million death annually. Thus, the development of new drugs is necessary. The viral enzyme reverse transcriptase (RT) represents a validated therapeutic target. Because the oxoquinolinic scaffold has substantial biological activities, including antiretroviral, a new series of 4-oxoquinoline ribonucleoside derivatives obtained by molecular hybridization were studied here. All synthesized compounds were tested against human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT), and 9a and 9d displayed the highest antiviral activities, with IC50 values of 1.4 and 1.6 µM, respectively. These compounds were less cytotoxic than AZT and showed CC50 values of 1486 and 1394 µM, respectively. Molecular docking studies showed that the most active compounds bound to the allosteric site of the enzyme, suggesting a low susceptibility to the development of antiviral resistance. In silico pharmacokinetic and toxicological evaluations reinforced the potential of the active compounds as anti-HIV candidates for further exploration. Overall, this work showed that compounds 9a and 9d are promising scaffold for future anti-HIV-1 RT drug design.
Assuntos
4-Quinolonas/farmacologia , Fármacos Anti-HIV/farmacologia , Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/efeitos dos fármacos , Inibidores da Transcriptase Reversa/farmacologia , Ribonucleosídeos/farmacologia , 4-Quinolonas/síntese química , 4-Quinolonas/química , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/química , Relação Dose-Resposta a Droga , Desenho de Fármacos , Transcriptase Reversa do HIV/metabolismo , HIV-1/metabolismo , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Estrutura Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Ribonucleosídeos/síntese química , Ribonucleosídeos/química , Relação Estrutura-AtividadeRESUMO
Tropical infectious diseases cause millions of deaths every year in developing countries, with about half of the world population living at risk. Mayaro virus (MAYV) is an emerging arbovirus that causes Mayaro fever, which is characterized by fever, headache, diarrhea, arthralgia, and rash. These symptoms can be clinically indistinguishable from other arboviruses, such as Dengue, Zika, and Chikungunya, which makes the diagnosis and treatment of the disease more difficult. Though, the Mayaro virus is a potential candidate to cause large-scale epidemics on the scale of ZIKV and CHIKV. Despite this, there is no licensed vaccine or antiviral for the treatment of Mayaro fever and most arboviruses, so the design and development of candidates for antiviral drugs are urgently needed. In this context, this mini-review aims to provide an overview of studies of anti-MAYV derivatives and highlight the importance of the discovery and development of promising drug candidates for Mayaro fever.
Assuntos
Infecções por Alphavirus/tratamento farmacológico , Alphavirus/efeitos dos fármacos , Alphavirus/fisiologia , Antivirais/farmacologia , Descoberta de Drogas , Antivirais/química , Antivirais/uso terapêutico , HumanosAssuntos
Acrocefalossindactilia/diagnóstico , Acrocefalossindactilia/genética , Heterozigoto , Mutação , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Adulto , Sequência de Aminoácidos , Sequência de Bases , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/patologia , Criança , Códon , Análise Mutacional de DNA , Fácies , Feminino , Estudos de Associação Genética , Humanos , Fenótipo , Conformação Proteica , Domínios Proteicos/genética , Radiografia , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/química , Tomografia Computadorizada por Raios XRESUMO
The assembly of a phenotype into modules or developmental fields, which are semiautonomous units in development and function, seems to be one of the strategies to increase the capacity to produce phenotypic variation. In mammals the upper dentition is formed on two distinct developmental units, wherein incisors are formed on the primary palate, which is derived from the embryonic frontonasal process, and the other teeth (canine, premolar, and molar) are formed on the alveolar bone, which is derived from the maxillary process (termed herein as PALATE2). The aim of the present work was to analyze the variations in size and number of premolar and molar teeth in primate dentition and to correlate these morphometrical parameters with the relative size of these tooth classes with respect to PALATE2. Furthermore, we seek to understand to what extent the changes in the relative size of premolar and molar fields can influence the size of each tooth within its respective field, and how these parameters connect with the variations in the dental formula that occurred during primate evolution. The data presented here not only indicate that premolar and molar fields can be seen as submodules of a larger and hierarchically superior module (i.e., PALATE2) but also present quantitative parameters that allow us to understand how variations in the relative size of premolar and molar teeth connect with the variations in the dental formula that occurred during primate evolution.