Non-Nucleoside HIV-1 Reverse Transcriptase Inhibitors: Synthesis and Biological Evaluation of Novel Quinoxalinylethylpyridylthioureas as Potent Antiviral Agents

Abstract

New heterocyclic derivatives of ethylpyridylthiourea, quinoxalinylethylpyridylthiourea (QXPT) and analogues, inhibited human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) activity and prevented HIV-1 cytopathogenicity in T4 lymphocytes. Several of these novel non-nucleoside RT inhibitors, with a substituted pyrroloquinoxalinone heteroaromatic skeleton, showed inhibitory activity against wild-type RT as well as against mutant RTs containing the single amino acid substitutions L100I, K103N, V106A, Y181I and Y188L that was much greater than other non-nucleoside inhibitors such as nevirapine. Maximum potency in enzymatic assays was achieved with a fluoropyrroloquinoxaline skeleton linked to the ethylpyridylthiourea moiety (FQXPT). In cell-based assays on different cell lines and on human monocyte-macrophages, 6-FQXPT exhibited EC50 values in the nanomolar range, with a promising selectivity index. Moreover, 6-FQXPT showed synergistic antiviral activity with zidovudine.

Quinoxalinylethylpyridylthioureas (QXPTs) as Potent Non-Nucleoside HIV-1 Reverse Transcriptase (RT) Inhibitors. Further SAR Studies and Identification of a Novel Orally Bioavailable Hydrazine-Based Antiviral Agent

“…In general, the halogenated analogues show greatly improved antienzymatic properties over their unsubstituted counterpart QXPT. 9 Furthermore, within this series, the antienzymatic potency and the broadening of spectrum of activity are also influenced by the nature of the heterocyclic skeleton (12e-g vs 6-FQXPT).…”

“…9 The azido intermediates 10a-g and 13a-g were obtained starting from the lactams 9a-g by direct alkylation with tosylethyl azide, while 13h (R ) 6-F, A ) CH, X ) N, Y ) C, and Z ) CH) and 13i (R ) 7,8-diMe, A ) CH, X ) N, Y ) C, and Z ) CH) were previously synthesized. 9 The lactams 9a-g were prepared according to previously described procedures. [10][11][12][13][14] Usually the O-alkylated products were obtained in 10-25% yield.…”

“…Antiviral activity of the tested compounds in acutely infected C8166 cultures was performed following an already described procedure. 9 The assay to evaluate anti-HIV drug efficacy in acutely infected mature macrophages has been previously described. 33 The antiviral activity of the compounds was assessed by measuring HIV-p24 antigen production in the supernatants of infected cultures as previously described 35 by using a commercially available HIV-antigen kit.…”

“…5-7a,b In the course of our research aimed at identifying novel antiviral agents, 8 we discovered that members of a series of quinoxalinylethylthioureas inhibited the replication of HIV-1 in different cell lines. 9 First, we identified the tricyclic quinoxaline system as a critical structural requirement for optimal interaction with the NNRTI binding site, and 6-FQXTP (6), a potent broad-spectrum secondgeneration NNRTI but characterized by unsatisfactory oral bioavailability, was selected as the lead compound. 9 To discover analogues with greater potency and better pharmacokinetic properties, we extended our structureactivity relationship (SAR) studies to assess the effect of a variety of substituents and heterocyclic systems (7) in place of the quinoxalinyl scaffold of 6-FQXPT (Chart 2).…”

Increased CD4 and CCR5 Expression and Human Immunodeficiency Virus Type 1 Entry in CD40 Ligand–Stimulated Macrophages

“…Soluble trimeric recombinant CD40L was provided by Immunex, and macrophage colony-stimulating factor (M-CSF) containing 2 £ 10 6 U/mg protein was provided by Genetics Institute. Zidovudine was purchased from Sigma Chemical, and 23f, a novel nonnucleoside reverse-transcriptase (RT) inhibitor [24], was a gift from G. Campiani (Dipartimento di Scienze Farmaceutiche, Università degli Studi di Siena, Siena, Italy).…”