RESUMO
The azaindole (AI) framework continues to play a significant role in the design of new antiviral agents. Modulating the position and isosteric replacement of the nitrogen atom of AI analogs notably influences the intrinsic physicochemical properties of lead compounds. The intra- and intermolecular interactions of AI derivatives with host receptors or viral proteins can also be fine tuned by carefully placing the nitrogen atom in the heterocyclic core. This wide-ranging perspective article focuses on AIs that have considerable utility in drug discovery programs against RNA viruses. The inhibition of influenza A, human immunodeficiency, respiratory syncytial, neurotropic alpha, dengue, ebola, and hepatitis C viruses by AI analogs is extensively reviewed to assess their plausible future potential in antiviral drug discovery. The binding interaction of AIs with the target protein is examined to derive a structural basis for designing new antiviral agents.
Assuntos
Influenza Humana , Vírus de RNA , Antivirais/química , Humanos , Influenza Humana/tratamento farmacológico , NitrogênioRESUMO
Adenosine A(2A) receptor (A(2A)R) antagonists have emerged as potential drug candidates to alleviate progression and symptoms of Parkinson's disease (PD), and reduce the dopaminergic side effects. The synthesis of novel compound 8-(furan-2-yl)-3-benzyl thiazolo [5,4-e][1,2,4] triazolo [1,5-c] pyrimidine-2-(3H)-thione (BTTP) was carried out to evaluate the potential of BTTP as A(2A)R antagonist using SCH58261, a standard A(2A)R antagonist. The strong interaction of BTTP with A(2A)R (ΔG=-12.46kcal/mol and K(i)=0.6nM) in silico analysis was confirmed by radioligand receptor binding studies showing high affinity (K(i)=0.004nM) and selectivity with A(2A)R (A(2A)/A(1)=1155-fold). The effect of CGS21680 (selective A(2A)R agonist) induced cAMP concentration (0.1pmol/ml) in HEK293 cells was antagonized with BTTP (0.065pmol/ml) and SCH58261 (0.075pmol/ml). Furthermore, BTTP pre-treated (5, 10 and 20mg/kg) haloperidol-induced mice demonstrated significant attenuation in catalepsy and akinesia. BTTP induced elevation in the striatal dopamine concentration (2.90µM/mg of tissue) was comparable to SCH58261 (2.92µM/mg of tissue) at the dose of 10mg/kg. The results firmly articulate that BTTP possesses potential A(2A)R antagonist activity and can be further explored for the treatment of PD.
Assuntos
Agonistas do Receptor A2 de Adenosina/farmacologia , Pirimidinas/farmacologia , Receptores A2 de Adenosina/metabolismo , Triazóis/farmacologia , Acridinas/farmacocinética , Adenosina/análogos & derivados , Adenosina/farmacologia , Agonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/farmacologia , Animais , Linhagem Celular Transformada , Cloroquinolinóis/farmacologia , Corpo Estriado/efeitos dos fármacos , AMP Cíclico/metabolismo , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Humanos , Camundongos , Modelos Moleculares , Fenetilaminas/farmacologia , Ligação Proteica/efeitos dos fármacos , Pirimidinas/química , Fatores de Tempo , Triazóis/química , Trítio/farmacocinéticaRESUMO
Novel thiazolotriazolopyrimidine derivatives (23-33) designed as potential adenosine A(2A) receptor (A(2A)R) antagonists were synthesized. Molecular docking studies revealed that all compounds (23-33) exhibited strong interaction with A(2A)R. The strong interaction of the compounds (23-33) with A(2A)R in silico was confirmed by their high binding affinity with human A(2A)R stably expressed in HEK293 cells using radioligand-binding assay. The compounds 24-26 demonstrated substantial binding affinity and selectivity for A(2A)R as compared to SCH58261, a standard A(2A)R antagonist. Decrease in A(2A)R-coupled release of endogenous cAMP in treated HEK293 cells demonstrated in vitro A(2A)R antagonist potential of the compounds 24-26. Attenuation in haloperidol-induced motor impairments (catalepsy and akinesia) in Swiss albino male mice pre-treated with compounds 24-26 further supports their role in the alleviation of PD symptoms.