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

Abstract

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-1(RF) 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, CH(3), and Br substituents and with diminished activity occurring with smaller (H and F) or larger (I and CF(3)) 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 EC(50) values for inhibition of the cytopathic effect of HIV-1(RF) 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.

Synthesis, Anti-HIV Activity, and Metabolic Stability of New Alkenyldiarylmethane HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

“…9 However, an attempted synthesis of 3-but-3-ynyl-1,3-oxazolidin-2-one (25) from 3-butyn-1-bromide or 3-butyn-1-iodide and 2-oxazolidinone failed due to an elimination reaction. In order to minimize the competitive elimination reaction, the halide leaving group was changed to a tosylate, which favors nucleophilic substitution over elimination when a competition between S N 2 and E2 processes is involved.…”

Identification of a Novel Scaffold for Allosteric Inhibition of Wild Type and Drug Resistant HIV-1 Reverse Transcriptase by Fragment Library Screening

“…They resemble substructures of the published NNRTIs 26 and 27 ( Figure 9). 21,25 Another way to investigate if fragments similar to known NNRTIs are more prone to bind to HIV-1 RT than dissimilar fragments is to create an enrichment plot based on the maximum Tversky similarity. This is done by first sorting the screened fragment library on the basis of maximum Tversky similarity, then plotting the cumulative percent of all hits recovered vs percent of library screened.…”

“…Examples of nonbinding fragments(21)(22)(23)(24)(25) representing substructures of published NNRTIs(3,(18)(19)(20) [22][23][24]. Compound 3 is delavirdine, one of the reference compounds used.…”

Design, Synthesis, Anti-HIV Activities, and Metabolic Stabilities of Alkenyldiarylmethane (ADAM) Non-nucleoside Reverse Transcriptase Inhibitors

“…20,22,23 Previous molecular modeling studies with ADAM 1 have indicated the possibility for either bifurcated hydrogen bonding between the side chain ester carbonyl of the ligand, the terminal amino group of Lys103, and the backbone amide N-H of Lys101 22 or hydrogen bonding to the backbone amide N-H of Lys101 only. 23 In the present case, the model displays a hydrogen bond from the side-chain ester carbonyl and Lys103 only, and this may result from displacement of the side chain more in the direction of Lys103 resulting from the larger steric bulk of a thioester group in 23 versus an ester group in 1. However, the general features of the model derived from 23 are similar to those seen with 1, and the two have the general "butterfly shape" seen in the X-ray crystal structures of nevirapine and a number of other NNRTIs.…”