RESUMO
Sixteen new C-terminally modified analogues of 2, a previously described potent and selective AT2R ligand, were designed, synthesized and evaluated for their affinity to the AT2R receptor. The introduction of large, hydrophobic substituents was shown to be beneficial and the most active compound (17, Ki=8.5 µM) was over 12-times more potent than the lead compound 2.
Assuntos
Isoleucina/síntese química , Isoleucina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Animais , Avaliação Pré-Clínica de Medicamentos/métodos , Células HEK293 , Humanos , Ligantes , Oligopeptídeos/síntese química , Oligopeptídeos/metabolismo , Ligação Proteica/fisiologia , SuínosRESUMO
The synthesis of original imidazo[1,2-a]pyridines bearing a thioether side chain at the 3 position and diversely substituted on the 6 or 8 position, and their antiviral activities are reported. From the synthesized compounds, the imidazo[1,2-a]pyridines bearing a 5 membered heterocycle (thiophene, furane or pyrrole) in the 6 position or a phenylthio group in the 6 or 8 position were the most potent against human cytomegalovirus (CMV) and varicella-zoster virus (VZV), whereas several other congeners, while less potent, were more selective in their inhibitory activity against VZV and CMV. These compounds showed similar activity against thymidine kinase competent (TK+) and deficient (TK-) VZV strains, demonstrating a mechanism of action independent of the viral thymidine kinase.
Assuntos
Antivirais/síntese química , Citomegalovirus/efeitos dos fármacos , Herpesvirus Humano 3/efeitos dos fármacos , Imidazóis/farmacologia , Piridinas/farmacologia , Antivirais/química , Antivirais/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Infecções por Citomegalovirus/tratamento farmacológico , Herpes Zoster/tratamento farmacológico , Humanos , Imidazóis/síntese química , Imidazóis/química , Pulmão/citologia , Pulmão/embriologia , Estrutura Molecular , Piridinas/síntese química , Piridinas/química , Relação Estrutura-AtividadeRESUMO
To study P1-P3 macrocyclizations of previously reported tertiary-alcohol-comprising HIV-1 protease inhibitors (PIs), three new 14- and 15-member macrocyclic PIs were designed, synthesized by ring-closing metathesis, and evaluated alongside with 10 novel linear PIs. Cocrystallized complexes of the macrocyclic PIs and the HIV-1 protease are presented, analyzed, and discussed. The macrocyclic structures exhibited higher activities than the linear precursors with Ki and EC50 values down to 3.1 nM and 0.37 µM, respectively.
Assuntos
Álcoois/química , Desenho de Fármacos , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/farmacologia , Protease de HIV/metabolismo , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Técnicas de Química Sintética , Cristalografia por Raios X , Protease de HIV/química , Inibidores da Protease de HIV/química , Compostos Macrocíclicos/química , Modelos Moleculares , Conformação ProteicaRESUMO
Using Ttou 84 as starting point, a novel class of biphenyl derivatives of imidazo[1,2-a]pyridine and imidazo[1,2-b]pyridazine was designed to optimize the inhibitory properties on the replication of the bovine viral diarrhoea virus (BVDV) and hepatitis C virus (HCV). Three sites of pharmacomodulation were chosen i.e. positions 2, 3 and 6 on the central heterocyclic core structure. From the 49 analogues tested, only compound 18j (3-(2'-hydroxybiphen-3-yl)-2-(2-methoxyphenyl)-6-(thien-3-yl)imidazo[1,2-b]pyridazine) showed antiviral activity in the HCV replicon system reminiscent of selective inhibition (60-70% inhibition). Compound 4f (3-(biphen-3-yl)-2-(4-fluorophenyl)-6-phenylthioimidazo[1,2-a]pyridine) proved to be the most selective inhibitor of BVDV replication and showed no or only marginal cross-resistance with known inhibitors of pestivirus replication. The cross-resistance profile of 4f might indicate that 4f does not interact with the same binding site as BPIP, VP32947, AG110 or LZ37. From 42 analogues tested against both viruses, QSAR studies were discussed in regard to BVDV antiviral activity.
Assuntos
Antivirais/farmacologia , Vírus da Diarreia Viral Bovina/efeitos dos fármacos , Hepacivirus/efeitos dos fármacos , Imidazóis/farmacologia , Piridazinas/farmacologia , Piridinas/farmacologia , Antivirais/síntese química , Antivirais/química , Relação Dose-Resposta a Droga , Imidazóis/síntese química , Imidazóis/química , Testes de Sensibilidade Microbiana , Estrutura Molecular , Piridazinas/síntese química , Piridazinas/química , Piridinas/síntese química , Piridinas/química , Relação Quantitativa Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
The NorA efflux pump lowers intracellular fluoroquinolone concentrations by expelling antibiotics through the membrane of Staphylococcus aureus. We identified 3-aryl-4-methyl-2-quinolin-2-ones as compounds able to restore the activity of the NorA substrate, ciprofloxacin, against resistant S. aureus strains, and acting as efflux pump inhibitors (EPI). In particular, 5-hydroxy-7-methoxy-4-methyl-3-phenylquinolin-2-one (6 c) presents both an EPI and an antimicrobial effect. Its efficacy and safety make it a potential candidate for further investigations.
Assuntos
Antibacterianos/farmacologia , Quinolonas/química , Staphylococcus aureus/efeitos dos fármacos , Animais , Antibacterianos/química , Antibacterianos/toxicidade , Proteínas de Bactérias/antagonistas & inibidores , Proteínas de Bactérias/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Ciprofloxacina/farmacologia , Farmacorresistência Bacteriana Múltipla , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Quinolonas/farmacologia , Quinolonas/toxicidade , Staphylococcus aureus/metabolismoRESUMO
The synthesis of original imidazo[1,2-a]pyridines bearing a phenethylthiomethyl side chain at the 3 position and a (hetero)aryl substituent on the 6 or 8 position, and their antiviral activities are reported. From the synthesized compounds, the 6-halogeno and 6-phenylimidazo[1,2-a]pyridine derivatives 4c-d and 5b were the most potent against human cytomegalovirus (CMV) and/or varicella-zoster virus (VZV), whereas several other congeners (i.e., 5e, 5g, 5i, 5l, 5n, 5p, 5q, and 5t), while less potent, were equally or more selective in their inhibitory activity against both VZV and CMV. These compounds showed similar activity against thymidine kinase competent (TK(+)) and deficient (TK(-)) VZV strains, demonstrating a mechanism of action independent of the viral thymidine kinase.