RESUMO
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed to treat inflammatory-related diseases, pain and fever. However, the prolong use of traditional NSAIDs leads to undesirable side effects such as gastric, ulceration, and renal toxicity due to lack of selectivity toward respective targets for COX-2, 5-LOX, and PDE4B. Thus, targeting multiple sites can reduce these adverse effects of the drugs and increase its potency. A series of methoxyflavones (F1-F5) were synthesized and investigated for their anti-inflammatory properties through molecular docking and inhibition assays. Among these flavones, only F2 exhibited selectivity toward COX-2 (Selectivity Index, SI: 3.90, COX-2 inhibition: 98.96 ± 1.47%) in comparison with celecoxib (SI: 7.54, COX-2 inhibition: 98.20 ± 2.55%). For PDEs, F3 possessed better selectivity to PDE4B (SI: 4.67) than rolipram (SI: 0.78). F5 had the best 5-LOX inhibitory activity among the flavones (33.65 ± 4.74%) but less than zileuton (90.81 ± 0.19%). Docking analysis indicated that the position of methoxy group and the substitution of halogen play role in determining the bioactivities of flavones. Interestingly, F1-F5 displayed favorable pharmacokinetic profiles and acceptable range of toxicity (IC50>70 µM) in cell lines with the exception for F1 (IC50: 16.02 ± 1.165 µM). This study generated valuable insight in designing new anti-inflammatory drug based on flavone scaffold. The newly synthesized flavones can be further developed as future therapeutic agents against inflammation.
Assuntos
Araquidonato 5-Lipoxigenase , Flavonas , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios não Esteroides/farmacologia , Araquidonato 5-Lipoxigenase/genética , Araquidonato 5-Lipoxigenase/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Ciclo-Oxigenase 2/genética , Inibidores de Ciclo-Oxigenase 2/farmacologia , Flavonas/farmacologia , Inibidores de Lipoxigenase/farmacologia , Simulação de Acoplamento Molecular , Estrutura Molecular , Inibidores de Fosfodiesterase/farmacologia , Relação Estrutura-AtividadeRESUMO
BACKGROUND: Despite the strategic development plan by the authorities for the Orang Asli, there are six subtribes of which their population numbers are small (less than 700). These minorities were not included in most of the health related studies published thus far. A comprehensive physiological and biomedical updates on these small subtribes in comparison to the larger subtribes and the urban Malay population is timely and important to help provide appropriate measures to prevent further reduction in the numbers of the Orang Asli. METHODS: A total of 191 Orang Asli from different villages in Peninsular Malaysia and 115 healthy urban Malays were recruited. Medical examinations and biochemical analyses were conducted. Framingham risk scores were determined. Data was analyzed using IBM SPSS Statistics, Version 20.0. RESULTS: A higher percentage of the Orang Asli showed high insulin levels and hsCRP compared to the healthy Malays denoting possible risk of insulin resistance. High incidences of low HDL-c levels were observed in all the Orang Asli from the six subtribes but none was detected among the urban Malays. A higher percentage of inlanders (21.1% of the males and 4.2% of the females) were categorized to have high Framingham Risk Score. CONCLUSIONS: Orang Asli staying both in the inlands and peripheries are predisposed to cardiovascular diseases and insulin resistance diabetes mellitus. The perception of Orang Asli being healthier than the urban people no longer holds. We believed that this information is important to the relevant parties in strategizing a healthier community of the Orang Asli to avoid the vanishing of the vulnerable group(s).
