DEVELOPMENT OF MULTIFUNCTIONAL CHEMOTHERAPEUTIC AGENTS

这项研究是由B博士发起和进行的。 Vithal Shetty是FDA的客座研究员， 这个项目的调查员。一种新的设计方法， 已经开发了抗微生物剂。的总体目的 程序是合理设计和合成的化合物， 具有抗细菌、抗病毒和抗真菌活性。 在合理设计中特别针对的是包膜病毒 如疱疹病毒和艾滋病病毒。新化合物具有新颖的 结构特征，包括已知的二聚体连接， 疏水性抗代谢药（例如，氨基金刚烷 类似物）通过非常亲水的桥。亲水 该分子的一部分对糖蛋白具有高亲和力 微生物细胞壁的组成部分。这种亲和力将提供 毒性部分的细胞表面，提供了一种机制， 有效的活动。存在抑制复制的可能性， 艾滋病病毒等病毒，并通过附着有毒的 病毒的外壳，一种杀死病毒的机制。使用 在这种策略下，对几种化合物进行了检查， 它们具有令人印象深刻的抗菌效力。一个强大的 双金刚烷胺类似物（B. V. Shetty，U. S.专利号 5，221，693）已通过NIH技术转让获得许可 作为一种广谱抗菌药物的开发计划， 特别是用于治疗牙龈感染。这种双功能 抗微生物药物设计的方法现已扩展到 包括将4-喹诺酮部分引入结构中。 选择4-喹诺酮类药物是因为它们对 原核生物DNA复制的抑制作用引起的 拓扑异构酶Ⅱ真核DNA复制要少得多 对喹诺酮抗菌剂的作用敏感。虽然 据报道，这些抗菌剂几乎没有或没有抗病毒 活动，这似乎可能是由于渗透性差， 病毒包膜通过亲脂性桥的合理连接， 已经开发了一种策略来递送4-喹诺酮部分 穿过病毒外壳铅化合物已被测试并发现 具有有效的抗艾滋病病毒和抗菌活性。工作是 目前正在优化这些先导化合物。

This research was initiated and carried out by Dr. B. Vithal Shetty, a guest researcher from the FDA who is co-principal investigator of this project. A novel approach to the design of new antimicrobial agents has been developed. The overall purpose of the program is the rational design and synthesis of compounds that have combined anti-bacterial, anti-viral and anti-fungal activity. Specifically targeted in the rational design are enveloped viruses such as herpes viruses and HIV. The new compounds have novel structural features which include a dimeric attachment of a known hydrophobic antimetabolite (for example, aminoadamantane analogues) through a very hydrophilic bridge. The hydrophilic portion of the molecule has a high affinity for glycoprotein components of the microbial cell wall. This affinity will deliver the toxic moieties to the cell surface, providing a mechanism for efficient activity. The potential exists for inhibition of replication of such viruses as HIV and, through the attachment of the toxic molecule to the viral coat, a mechanism for killing the virus. Using this strategy, several compounds were examined and certain of these possessed impressive antimicrobial potency. One potent bis-adamantamine analogue (B.V. Shetty, U. S. Patent No. 5,221,693) has been licensed through the NIH technology transfer program for development as a broad spectrum antimicrobial drug, especially for the treatment of gingival infections. This bifunctional approach to antimicrobial drug design has now been extended to include incorporation of 4-quinolone moieties into the structures. The choice of 4-quinolones stems from their selective effects on prokaryotic DNA replication caused by inhibition of the action of topoisomerase II. Eukaryotic DNA replication is much less susceptible to the action of quionolone antibacterials. Although these antibacterials are reported to have little or no anitviral activity, it seems likely that this is due to poor penetration of the viral envelope. By rational attachment of lipohilic bridges, a strategy has been developed to deliver the 4-quinolone moiety across the viral coat. Lead compounds have been tested and found to have potent anti-HIV, as well as antibacterial acitivity. Work is now in progress to optimize these lead compounds.