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

Abstract

Quinoxalinylethylpyridylthioureas (QXPTs) represent a new class of human immunodeficiency virus type 1 (HIV-1) non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) whose prototype is 6-FQXPT (6). Docking studies based on the three-dimensional structure of RT prompted the synthesis of novel heteroarylethylpyridylthioureas which were tested as anti-HIV agents. Several compounds proved to be potent broad-spectrum enzyme inhibitors and significantly inhibited HIV-1 replication in vitro. Their potency depends on the substituents and the nature of the heterocyclic skeleton linked to the ethyl spacer, and structure-activity relationships are discussed in terms of the possible interaction with the RT binding site. Although the new QXPTs analogues show potent antiviral activity, none of the compounds tested overcome the pharmacokinetic disadvantages inherent to ethylpyridylthioureidic antiviral agents, which in general have very low oral bioavailability. Through an integrated effort involving synthesis, docking studies, and biological and pharmacokinetic evaluation, we investigated the structural dependence of the poor bioavailability and rapid clearance within the thioureidic series of antivirals. Replacing the ethylthioureidic moiety with a hydrazine linker led to a new antiviral lead, offering promising pharmacological and pharmacokinetic properties in terms of antiviral activity and oral bioavailability.

Synthesis and biological evaluation of novel substituted pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of the human protein kinase CK2

“…These compounds have been reported to serve as key intermediates for the assembly of several heterocycles including antipsychotic agent [13], anti-HIV agent [14], adenosine A 3 receptor modulator [15], antiparasitic agents [16e20], and antitumor agents [21,22]. In this last field, the discovery and development of novel therapeutic agents are one of the most important goals in medicinal chemistry.…”

Living on pyrrolic foundations – Advances in natural and artificial bioactive pyrrole derivatives

“…The interest in this class of compounds is driven by their vast potential for affecting our bodies, effecting either positive or negative changes. In the latter case, they are employed to treat cancer [7,17,18], HIV [19,20] and malaria [21], as well as act as psychotropic [22], antibacterial [10] and antifungal agents [23]. Considering alkaloids containing a pyrrole ring as a constituent of their structure, alkaloids obtained from marine creatures are of particular interest [4e10].…”

“…The report details several routes for the preparation of pyrrolostain (17), clorobiocin, pyoluteorin (18), staurosporine (19), rebeccamycin (20), chromoviridans (21), as well as a biosynthetic pathway to tetrapyrroles. Tetrapyrroles (Fig.…”

New anti‐HIV agents and targets

“…110 UC-781 would seem an ideal candidate for application as a vaginal microbicide (virucide), i.e., when formulated in replens gel. 111 To the new classes of NNRTIs that offer potent anti-HIV-1 activity belong the thieno [3,4-e][1,2,4]thiadiazine derivative QM96521, 112 the quinoxaline GW420867X, 113 the imidazole derivative S-1153 (AG1549, capravirine), [114][115][116] the quinoxalinylethylpyridyl thioureas (QXPTs), 126 the emivirine (MKC-442) derivative SJ-3366, 127 and R165335(TMC125). 128 As a rule, the ''new'' (''second'' generation) NNRTIs exhibit higher potency than the ''old'' (''first'' generation) NNRTIs against wild-type and NNRTI-resistant HIV-1.…”