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. Specificically targeted in the rational design are enveloped viruses such as herpes viruses and HIV. These compounds have novel structural features which include a dimeric attachment of a known hydrophobic antimetabolite (for example, aminoadamantane analogues) through a very hydrophilic bridge. These structural features combine to provide the potential for a novel mechanism for attachment of the toxic moiety to microbial organisms. Thus, 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. For example, 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. Initial testing of several bisadamentamine analogues (U.S. Patent No. 5,221, 693) revealed potent activity against gram positive and gram negative bacteria, fungi, yeast and enveloped viruses. Such combined activity potentially could be extremely useful in treatment of immunosuppressed patients. Two compounds were found to be very active against an amoeba called acanthamoeba polyphargia cyst. Current modifications to these prototypical molecules include introduction of a sulfoxide group in the bridging alkylene group to provide increased hydrophilic interactions. Also, aromatic rings have been introduced adjacent to the adamantane rings. These modifications have led to marked improvement in the level of anti-viral activity, and concomitant reduce cytotoxicity. For example, a bis-Schiff base prepared from 2- adamantanone and 4,4'-diaminophenylsulfone has been found to have potent activity against HIV infection in vitro.
