N-[2-(1-cyclohexenyl)ethyl]-N′-[2-(5-bromopyridyl)]-thiourea and N′-[2-(1-cyclohexenyl)ethyl]-N′-[2-(5-chloropyridyl)]- thiourea as potent inhibitors of multidrug-resistant human immunodeficiency virus-1

Uckun, Fatih M.; Chen, Mao; Pendergrass, Sharon; Maher, Danielle; Zhu, Dan; Tuel‐Ahlgren, Lisa; Venkatachalam, T. K.

doi:10.1016/s0960-894x(99)00460-6

Cited by 46 publications

(14 citation statements)

References 8 publications

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“…As predicted PHI-346 was a potent inhibitor of drug sensitive and drug-resistant HIV-1 strains ( Table 2) [95]. Functionalization at the 5 -position of the pyridyl ring of cyclohexenyl ring-containing thioureas with a Br atom led to a significant increase in anti-HIV activity as well as gain of spermicidal function [29,30].…”

Section: Phi-346 (N-[2-(1-cyclohexenyl)ethyl]-n'-[2-(5-bromopyridyl)]mentioning

confidence: 60%

“…The preferred compounds were 5-bromo (PHI-346) and 5-chloro (PHI-445) functionalized cyclohexenyl ring-substituted thioureas (Fig. 5) [30,95].…”

Section: Phi-346 (N-[2-(1-cyclohexenyl)ethyl]-n'-[2-(5-bromopyridyl)]mentioning

confidence: 99%

“…7A). PHI-346 makes 94 hydrophobic contacts with the surrounding RT residues, including P95, Y181, L100, V179, and Y188, which translates into a 3.0 log unit gain in the final interaction score [95]. A region in Wing 1 is compatible with polar atoms, which corresponds to the predicted location of the bound halogen atoms of PHI-346 (Br) and PHI-445 (Cl).…”

Section: Phi-346 (N-[2-(1-cyclohexenyl)ethyl]-n'-[2-(5-bromopyridyl)]mentioning

confidence: 99%

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Novel Broad-Spectrum Thiourea Non-Nucleoside Inhibitors for the Prevention of Mucosal HIV Transmission

D’Cruz

Uckun²

2006

CHR

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Non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTI) are an integral part of combination therapy comprising three classes of antiretroviral drugs for the management of HIV/AIDS. NNRTIs are chemically diverse compounds that bind to a common allosteric site of HIV-1 RT and noncompetitively inhibit DNA polymerization. Resistance to NNRTIs arises rapidly upon drug treatment and results from mutation of the amino acids lining the HIV-1 RT binding pocket. Nevertheless, rationally designed NNRTIs deduced from changes in binding pocket size, shape, and residue character that result from clinically observed NNRTI resistance mutations exhibit broad-spectrum anti-HIV-1 activity. Notably, membrane permeable tight binding NNRTIs have utility as topical microbicides since they are capable of blocking cell-free and cell-associated mucosal HIV-1 infection without metabolic activation. This review summarizes the discovery of highly potent tight binding phenethyl-thiazolyl-thiourea (PETT) derivatives targeting the NNI binding pocket of HIV-1 RT. These NNRTIs were rationally designed by molecular docking using a composite binding pocket constructed by superimposing the crystal structure coordinate data of several NNI/RT ligand-binding site complexes. Molecular modeling and score functions such as molecular surface area, the buried surface, and binding affinity values were used to analyze how drug-resistant mutations would change the RT binding pocket shape, volume, and chemical make-up of these NNRTIs, and how these changes could affect drug binding. Several ligand derivatization sites were identified for docked compounds that fit the binding pocket. The best fit was determined by calculating an inhibition constant (Ludi Ki) of the docked compound for the composite binding pocket. Compounds with a Ludi Ki of <1 microM were identified as the most promising tight binding NNRTIs. This review highlights novel lipophilic thiourea NNRTIs that display high binding affinity and selective indices with robust anti-HIV-1 activity against the wild type as well as drug-resistant isolates carrying multiple RT gene mutations. The increasing prevalence of drug-escape mutants among recent HIV seroconverters makes the discovery of these broad-spectrum thiourea NNRTIs useful as a component of topical microbicide for the prevention of mucosal HIV transmission.

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Section: Phi-346 (N-[2-(1-cyclohexenyl)ethyl]-n'-[2-(5-bromopyridyl)]mentioning

confidence: 60%

“…The preferred compounds were 5-bromo (PHI-346) and 5-chloro (PHI-445) functionalized cyclohexenyl ring-substituted thioureas (Fig. 5) [30,95].…”

Section: Phi-346 (N-[2-(1-cyclohexenyl)ethyl]-n'-[2-(5-bromopyridyl)]mentioning

confidence: 99%

Section: Phi-346 (N-[2-(1-cyclohexenyl)ethyl]-n'-[2-(5-bromopyridyl)]mentioning

confidence: 99%

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Novel Broad-Spectrum Thiourea Non-Nucleoside Inhibitors for the Prevention of Mucosal HIV Transmission

D’Cruz

Uckun²

2006

CHR

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show abstract

“…These findings indicate that, when compared to TRV analogues, double substitutions at axial or equatorial positions on these heterocyclic rings could lead to PETT derivatives with a broader range of curvatures, and that they would also better fit to Wing 2 region. (Uckun et al, 1999a) decided to replace the pyridyl ring of TRV by an aciclyc cyclohexenyl, adamantly or cis-myrtanyl ring. Such a proposal of modifications was due to the fact that these chosen groups would fit well with Wing 2 region of the NNI binding pocket.…”

Section: Rational Design Of New Pett Analoguesmentioning

confidence: 99%

Thiourea Derivatives: A Promising Class Against HIV/TB Co-Infection

Souza¹,

Bispo²,

Gonçalves³

et al. 2011

Global View of HIV Infection

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“…Phenethylthiazoylthiourea (PETT) compounds have been discovered as potent inhibitors of HIV type 1 and display certain structureactivity relationships among various substituents in their structure [105][106][107][108][109][110][111][112][113]. Furthermore, thiourea derivatives have been found to be potent and selective viral inhibitors, antifungal and antibacterial compounds [114][115][116][117][118][119][120][121].…”

Section: Biological Activities 3 Selenoureasmentioning

confidence: 99%