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Synthesis and structure activity relationship studies of non-nucleoside HIV-1 reverse transcriptase inhibitors
Uppsala University, Medicinska vetenskapsområdet, Faculty of Pharmacy, Department of Pharmaceutical Chemistry.
1999 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

HIV-1 reverse transcriptase (RT) is a target for anti-HIV chemotherapy. A series of PETT PhenylEthylThiazoleThiourea) non-nucleoside HIV-1 RT inhibitors were synthesised. All compounds were tested in an HIV-1 RT enzyme assay, and in cell culture using MT-4 cells and wild-type virus. Many compounds were also tested in HIV-1 RT enzyme assays with three constructed mutants, Ile100, Cys181 and Asn103, and in cell culture using virus containing a mutation in residue 100, 181 or 103.

The lead PETT compound, N-(2-phenethyl)-N'-(2-thiazolyl)thiourea, has an IC50 of 0.9 µM in an HIV-1 RT enzyme assay and an ED50 of 1.3 µM in an HIV-1 cell culture assay. The optimisation of this compound resulted in a clinical candidate, trovirdine, N-[2-(2-pyridylethyl)]-N'-[2-(5-bromopyridyl)]thiourea, which inhibits HIV-1 RT with an IC50 of 15 nM and has an ED50 of 20 nM in cell culture. Further optimisation produced more potent thiourea compounds comprising 2, 3, 6-trisubstituted phenethyl 5-chloro, 5-bromo or 5-cyano-2-pyridyl thiourea analogs. The IC50 and ED50 values of the most active of these analogs were 1 to 5 nM. Bioisosteric substitution of the thiourea moiety of PETT compounds with cyanoguanidine, guanidine and sulfonyldiamide is studied. Finally, the synthesis and structure activity relationship studies of highly potent, conformationally restricted, racemic and enantiomeric cyclopropyl urea analogs are described with enhanced antiviral activities even on mutant form of HIV-1 virus in the nanomolar range.

The three-dimensional structures of complexes between HIV-1 RT and an enantiomeric pair of cyclopropyl compounds have been determined. The structures show similar binding in the NNI binding pocket. The cyclopropyl moiety of both enantiomers has close-packing interactions with leucine residue 100, valine residue 179 and tyrosine residue 181, but in addition to these interactions the cyclopropyl moiety of the (+)-enantiomer has extensive hydrophobic close-packing interactions with glutamine residue 1138.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 1999. , 48 p.
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy, ISSN 0282-7484 ; 215
Keyword [en]
Pharmaceutical chemistry
Keyword [sv]
Farmaceutisk kemi
National Category
Medicinal Chemistry
Research subject
Organic Pharmaceutical Chemistry
URN: urn:nbn:se:uu:diva-1193ISBN: 91-554-4565-9OAI: oai:DiVA.org:uu-1193DiVA: diva2:160747
Public defence
1999-12-10, lecture hall B42, Biomedical Center, Uppsala, Uppsala, 10:15
Available from: 1999-11-19 Created: 1999-11-19Bibliographically approved

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