Inhibition of Clinically Relevant Mutant Variants of HIV-1 by Quinazolinone Non-Nucleoside Reverse Transcriptase Inhibitors

Abstract

A series of 4-alkenyl and 4-alkynyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones were found to be potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) of human immunodeficiency virus type-1 (HIV-1). The 4-alkenyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones DPC 082 and DPC 083 and the 4-alkynyl-3, 4-dihydro-4-(trifluoromethyl)-2-(1H)-quinazolinones DPC 961 and DPC 963 were found to exhibit low nanomolar potency toward wild-type RF virus (IC(90) = 2.0, 2.1, 2.0, and 1.3 nM, respectively) and various single and many multiple amino acid substituted HIV-1 mutant viruses. The increased potency is combined with favorable plasma serum protein binding as demonstrated by improvements in the percent free drug in human plasma when compared to efavirenz: 3.0%, 2.0%, 1.5%, 2. 8%, and 0.2-0.5% for DPC 082, DPC 083, DPC 961, DPC 963, and efavirenz, respectively.

Synthesis and in vivo anticancer and antiangiogenic effects of novel thioxothiazolidin-4-one derivatives against transplantable mouse tumor

“…A wide spectrum of pharmacological activities has been reported for these compounds. Some of these therapeutic areas include antimicrobial (Franzen, 2000), anticancer (Lakhan and Rai, 1987;Hour et al, 2000), antiviral (Hamel et al, 1996), anticonvulsant (Corbett et al, 2000;Archana et al, 2003), antifungal (Samir et al, 2007;Bartroli et al, 1998), antiinflammatory (Goel et al, 1999), analgesic (Smith and Dewitt, 1996), and antiproliferative activities (Herschman, 1996;Veeresa et al, 2004). Thiazolidinones derivatives possess broad pharmacological action on the central nervous system, especially anti-HIV agents (Barreca et al, 2001) and cyclooxygenase (COX) inhibitors (Chen et al, 2004).…”

Synthesis and in vitro antiproliferative activity against human cancer cell lines of novel 5-(4-methyl-benzylidene)-thiazolidine-2,4-diones

“…A wide range of pharmacological activities has been attributed to these molecules. Among these include antimicrobial [5], anticancer [6,7], antiviral [8], anticonvulsant [9,10], antitubercular [11], antifungal [12,13], anti-inflammatory [14], analgesic [15] and antiproliferative [16,17] activities. Thiazolidinone derivatives possess wide range of pharmacological action on central nerves system, especially on anti-HIV agents [18] and cyclooxygenase (COX) inhibitors [19].…”

Diammonium hydrogen phosphate: a versatile and inexpensive reagent for one-pot synthesis of dihydropyrimidinones, quinazolinones and azalactones under solvent-free conditions

“…Interest in the synthesis of many substituted quinazolinones has been renewed owing to their potential use as physiologically active compounds [16,17] such as antibiotics [18], and potent non-nucleoside reverse transcriptase inhibitors of the human immunodeficiency virus (HIV-1) [19]. A number of synthetic methods for the preparation of substituted (3H)-quinazolin-4-ones have been described [20][21][22][23][24][25].…”