A current need exists for novel non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) that: 1) have lower toxicities than the existing NNRTIs, 2) have unique resistance mutation profiles and remain active against mutant reverse transcriptases that are resistant to the existing NNRTIs, 3) have the ability to suppress the emergence of resistant viral strains when used in combination with other anti-HIV agents, 4) have synergistic anti-HIV activity in combination with other anti-HIV agents, 5) are metabolically more stable than the existing ADAMs and therefore have enhanced bioavailabilities, 6) have a wide range of activity vs. various HIV-1 strains, and 7) have high affinities for RT, and therefore have the potential for high anti-HIV potency. Our research group has recently reported the design and synthesis of a novel series of alkenyldiarylmethane (ADAM) NNRTIs that are potent inhibitors of the cytopathic effect of HIV-1. Although some of the ADAMs inhibit the cytopathic effect of HIV-1RF in CEM-SS cell culture at low nanomolar concentrations, the potential therapeutic utility of the ADAMs is compromised by the presence of three methyl ester moieties that are readily hydrolyzed by plasma esterases. Consequently, the main goal of the present project is to find suitable replacements for these three labile esters that will be metabolically stable and will also retain the potent anti-HIV activity of the parent compound. Preliminary studies have shown promising activity resulting from oxazolidinone and methyl ether replacements of the methyl esters, and a variety of additional metabolically stable moieties are proposed. These include ethyl ketone, isobutylene, enol ether, ether, vinyl ketone, n-propyl, alpha, alpha -difluoroketone, difluoroenol ether, tetrafluoroisobutylene, difluoroisobutylene, imidoyl fluoride, amide, thioester, thionoester, and dithioester replacements. Syntheses are proposed for ADAMs containing each of these structurally simple methyl ester replacements. The hydrolytic stabilities of the new ADAMs will be investigated in human plasma. In addition, the anti-HIV activities of the new ADAMs will be determined in a variety of biological systems. The potencies of the compounds as inhibitors of the cytopathic effect of a variety of HIV-1 strains will be determined in cell culture. The cytotoxicities of the compounds in uninfected lymphocytes will also be investigated. The enzyme inhibitory activities of the ADAMs will be established in cell-free systems using both wild type and mutant proteins. Mechanism of action studies will include both time-of-addition (time course) studies as well as the examination of the compounds in a number of assays employing targets that represent various stages in the replication cycle of the virus. The synergistic activities of the compounds with existing anti-HIV agents will be established. The activities of the ADAMs vs. NNRTI resistant viruses will be investigated. The aqueous solubilities of the new ADAMs will be measured accurately.
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