DEVELOPMENT OF MULTIFUNCTIONAL CHEMOTHERAPEUTIC AGENTS

这项研究是由B博士发起并进行的。 Vithal Shetty，FDA的客座研究员，联合负责人 这个项目的调查员。一种新的设计新方法 抗菌剂已经开发出来了。该计划的总体目的是 程序是对化合物的合理设计和合成， 具有抗菌、抗病毒和抗真菌活性。 Rational设计中特别针对的是包膜病毒 例如疱疹病毒和艾滋病毒。这些新化合物具有新奇的特性 结构特征，包括已知的二聚体连接 疏水性抗代谢物(例如，氨基金刚烷 类似物)通过非常亲水的桥。亲水性 分子的一部分对糖蛋白有很高的亲和力。 微生物细胞壁的组成部分。这种亲和力将为 细胞表面的有毒部分，提供了一种机制 高效的活动。存在抑制复制的可能性 像HIV这样的病毒，通过附着有毒的 分子附着在病毒外壳上，这是一种杀死病毒的机制。vbl.使用 这一策略，检查了几种化合物，并确定了 这些化合物具有令人印象深刻的抗菌效力。一个强大的力量 双金刚胺类似物(B.V.Shetty，美国专利号 5,221,693)已通过NIH技术转让获得许可 作为广谱抗菌药的开发计划， 尤其适用于牙周感染的治疗。这种双功能 抗菌药物设计的方法现已扩展到 包括将4-喹诺酮基团掺入结构中。 选择4-喹诺酮类药物是因为它们对 抑制蛋白作用引起的原核细胞DNA复制 拓扑异构酶II.真核DNA复制要少得多 易受喹诺酮类抗菌药物作用的。虽然 据报道，这些抗菌药很少或根本没有抗病毒作用。 活动，这似乎是由于渗透率较低 病毒信封。通过合理地连接亲脂桥，一种 已经制定了策略来传递4-喹诺酮部分 穿过病毒式的外套。已经测试并发现了铅化合物 具有强大的抗HIV，以及抗菌活性。工作是 目前正在进行优化这些先导化合物的工作。

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.