RESUMO
A series of new imidazo[1,2-a]pyridine linked with thiazole/thiophene motif through a keto spacer were synthesized and tested for their cytotoxic potential against three human cancer cell lines including A549, HeLa and U87-MG using MTT assay. Compounds A2, A3, A4, C1 and C2 showed cytotoxicity against all the three cell lines. The selectivity index for compound A4 for A549 and HeLa cells was comparable to that of doxorubicin. Among the synthesized compounds, B5 showed the maximum inhibition of NF-κB activity as ascertained by NF-κB reporter assay (IC50â¯=â¯6.5⯱â¯0.6⯵M). Treatment of NCI-H23 cells (EGFR overexpressed, KRAS G12V mutant) with erlotinib and gefitinib along with compounds A4 and B5 indicated synergistic and additive potential of combination therapy.
Assuntos
NF-kappa B/antagonistas & inibidores , Piridinas/química , Tiazóis/química , Tiofenos/química , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , NF-kappa B/metabolismo , Piridinas/síntese química , Piridinas/farmacologia , Relação Estrutura-AtividadeRESUMO
Here we report novel thiazole-thiophene conjugates as adenosine receptor antagonists. All the molecules were evaluated for their binding affinity for adenosine receptors. Most of the molecules were found to interact with the A1, A2A and A3 adenosine receptor subtypes with good affinity values. The most potent and selective compound 8n showed an A3Ki value of 0.33µM with selectivity ratios of >90 versus the A1 and >30 versus the A2 subtypes. For compound 8n docking studies into the binding site of the A3 adenosine receptor are provided to visualize its binding mode.
Assuntos
Antagonistas de Receptores Purinérgicos P1/síntese química , Receptores Purinérgicos P1/química , Tiazóis/química , Tiofenos/química , Sítios de Ligação , Domínio Catalítico , Cinética , Simulação de Acoplamento Molecular , Ligação Proteica , Antagonistas de Receptores Purinérgicos P1/química , Antagonistas de Receptores Purinérgicos P1/metabolismo , Receptor A1 de Adenosina/química , Receptor A1 de Adenosina/metabolismo , Receptor A3 de Adenosina/química , Receptor A3 de Adenosina/metabolismo , Receptores A2 de Adenosina/química , Receptores A2 de Adenosina/metabolismo , Receptores Purinérgicos P1/metabolismo , Relação Estrutura-AtividadeRESUMO
The stability of the drug actarit was studied under different stress conditions like hydrolysis (acid, alkaline and neutral), oxidation, photolysis and thermal degradation as recommended by International Conference on Harmonization (ICH) guidelines. Drug was found to be unstable in acidic, basic and photolytic conditions and produced a common degradation product while oxidative stress condition produced three additional degradation products. Drug was impassive to neutral hydrolysis, dry thermal and accelerated stability conditions. Degradation products were identified, isolated and characterized by different spectroscopic analyses. Drug and the degradation products were synthesized by a new route using green chemistry. The chromatographic separation of the drug and its impurities was achieved in a phenomenex luna C18 column employing a step gradient elution by high performance liquid chromatography coupled to photodiode array and mass spectrometry detectors (HPLC-PDA-MS). A specific and sensitive stability-indicating assay method for the simultaneous determination of the drug actarit, its process related impurities and degradation products was developed and validated.
