The Biological Effects of Structural Variation at the Meta Position of the Aromatic Rings and at the End of the Alkenyl Chain in the Alkenyldiarylmethane Series of Non-Nucleoside Reverse Transcriptase Inhibitors

• Published in: Journal of medicinal chemistry Vol. 44; no. 24; pp. 4092 - 4113
• Main Authors: Xu, Guozhang, Micklatcher, Mark, Silvestri, Maximilian A, Hartman, Tracy L, Burrier, Jennifer, Osterling, Mark C, Wargo, Heather, Turpin, Jim A, Buckheit, Robert W, Cushman, Mark
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 22.11.2001; Amer Chemical Soc
• Subjects: Alkenes - chemical synthesis; Alkenes - chemistry; Alkenes - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Benzene Derivatives - chemical synthesis; Benzene Derivatives - chemistry; Benzene Derivatives - pharmacology; Biological and medical sciences; Cell Line; Chemistry, Medicinal; Cytopathogenic Effect, Viral; Drug Resistance, Multiple; Drug Resistance, Viral; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - genetics; HIV-1 - drug effects; HIV-1 - isolation & purification; Humans; In Vitro Techniques; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - enzymology; Leukocytes, Mononuclear - virology; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Monocytes - drug effects; Monocytes - enzymology; Monocytes - virology; Mutagenesis, Site-Directed; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Science & Technology; Structure-Activity Relationship; Virus Replication; VIRUS TYPE-1 HIV-1; SELECTIVE-INHIBITION; ADAM SERIES; PHARMACOKINETICS; LOW-VALENT TITANIUM; COMBINATION THERAPY; RESISTANCE; ANTIRETROVIRAL THERAPY; INFECTION; COENZYME-A; RNA-directed DNA polymerase; HIV-1 virus; Enzyme; Aliphatic compound; Transferases; Non nucleoside compound; Retroviridae; Enzyme inhibitor; Inhibitor enzyme complex; Binding site; Lentivirus; In vitro; Modeling; Virus; Benzoic acid derivatives; Nucleotidyltransferases; Structure activity relation; Reverse transcriptase inhibitor; Molecular model; Antiviral; Human immunodeficiency virus; Chemical synthesis; Halogen Organic compounds
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm010212m

In an effort to elucidate a set of structure−activity relationships in the alkenyldiarylmethane (ADAM) series of non-nucleoside reverse transcriptase inhibitors, a number of modifications were made at two locations:  (1) the meta positions of the two aromatic rings and (2) the end of the alkenyl chain. Forty-two new ADAMs were synthesized and evaluated for inhibition of the cytopathic effect of HIV-1RF in CEM-SS cell culture and for inhibition of HIV-1 reverse transcriptase. The size of the aromatic substituents was found to affect anti-HIV activity, with optimal activity appearing with Cl, CH3, and Br substituents and with diminished activity occurring with smaller (H and F) or larger (I and CF3) substituents. The substituents at the end of the alkenyl chain were also found to influence the antiviral activity, with maximal activity associated with methyl or ethyl ester groups and with diminished activity resulting from substitution with higher esters, amides, sulfides, sulfoxides, sulfones, thioesters, acetals, ketones, carbamates, ureas, and thioureas. Twelve of the new ADAMs displayed submicromolar EC50 values for inhibition of the cytopathic effect of HIV-1RF in CEM-SS cells. Selected ADAMs, 19 and 21, were compared to previously published ADAMs 15 and 17 for antiviral efficacy and activity against the HIV-1 reverse transcriptase enzyme. All four ADAMs were found to inhibit HIV-1 reverse transcriptase enzyme activity, to inhibit the replication of a variety of HIV-1 clinical isolates representing syncytium-inducing, nonsyncytium-inducing, and subtype representative isolates, and to inhibit HIV-1 replication in monocytes. Subsequent assessment against a panel of site-directed reverse transcriptase mutants in NL4-3 demonstrated no effect of the K103N mutation on antiviral efficacy and a slight enhancement (6- to 11-fold) in sensitivity to AZT-resistant viruses. Additionally, ADAMs 19 (44-fold) and 21 (29-fold) were more effective against the A98G mutation (found in association with nevirapine resistance in vitro), and ADAM 21 was 5-fold and 2-fold more potent against the Y181C inactivation mutation than the previously reported ADAMs 15 and 17, respectively. All four ADAMs were tested for efficacy against a multidrug-resistant virus derived from a highly experienced patient expressing resistance to the reverse transcriptase enzyme inhibitors AZT, ddI, 3TC, d4T, foscarnet, and nevirapine, as well as the protease inhibitors indinavir, saquinavir, and nelfinavir. ADAM 21 was 2-fold more potent than ADAM 15 and 6-fold more potent than ADAMs 17 and 19 at preventing virus replication. Thus, we have identified a novel series of reverse transcriptase inhibitors with a favorable profile of antiviral activity against the primary mutation involved in clinical failure of non-nucleoside reverse transcriptase inhibitors, K103N, and that retain activity against a multidrug-resistant virus.