I. Synthesis and Anti-influenza Activities of Novel Baicalein and Daidzein Analogs;II. Facile One-pot Synthesis and Anti-inflammatory Activity of Novel Benzopyran Derivatives

• Main Authors: Shu-Ting Chung, 鍾淑婷
• Other Authors: An-Rong Lee
• Format: Others
• Language: zh-TW
• Published: 2015
• Online Access: http://ndltd.ncl.edu.tw/handle/gm7755

博士 === 國防醫學院 === 醫學科學研究所 === 103 === I. Influenza viruses are the most significant source of viral respiratory infections in humans worldwide, causing recurrent epidemics and global pandemics that bring about severe morbidity and mortality involving millions of people annually. Unfortunately, recent studies have indicated that pandemic H1N1 Tamiflu-resistant (H1N1 TR) viral isolates have been progressively rising, which may pose a risk to the increase of fatality in human beings. This means that development of new therapeutic agents are urgently needed and prompted us to synthesize some novel flavonoids and explore the possibility as potential anti-influenza agents. Two series of flavonoids, baicalein and daidzein analogs, were synthesized, based on modification of the active ingredients of traditional Chinese Medicines (TCMs), and screened for anti-influenza activity. The synthetic baicalein (flavone) analogs, especially with the B-rings substituted with bromine atoms, were much more potent than the isoflvonoids or oseltamivir or ribavirin against H1N1 Tamiflu-resistant virus. The most promising were 5b, 5c, 6b and 6c, all displaying an EC50 at around 4.0–4.5 μM, and a selective index (SI) > 70. For seasonal H3N2-infected influenza virus, both 5a and 5b with SI > 17.3 indicated superior to ribavirin. The flavonoids having both not-naturally-occurring bromo-substituted B-rings and appropriate hydroxyls positioning on the A-rings might be critical in determining the activity and selectivity against H1N1-Tamiflu-resistant infected influenza viruses. II. The need to develop new and safer therapeutic agents has motivated the present design and synthesis of two series of novel substituted 4H-chromene and chromeno[2,3-b]pyridine derivatives as potential anti-inflammatory agents which, in our laboratory, were efficiently prepared, under microwave irradiation, in a one-pot reaction and evaluated for their anti-inflammatory activities. Comparing with quercetin, six compounds (1b, 1c, 1h, 2d, 2j and 2l) out of the synthetic products displayed more potent inhibitory activity against tumor necrosis factor (TNF)-α-induced nitric oxide (NO) production and comparable cell viability in both human and porcine chondrocytes based on the MTT results. Additionally, 2d indicated very potent anti-inflammatory effect by suppression of the formation of carrageenan-induced rat paw edema and prostaglandin E2 (PGE2) at the dosages of 10 and 20 mg/kg, respectively. The results herein suggest that these novel compounds may have potential as structural templates in the subsequent design and development of new anti-inflammatory drugs.