title: Structure-activity relationship studies on potential non-nucleoside DABO-like inhibitors of HIV-1 reverse transcriptase.
abstract: Using 2,6-dichloro-4-aminopyrimidine, a number of uracil and cytosine derivatives with both arylthio and alkoxy moieties were prepared. These novel pyrimidines share chemical similarities with DABOs and HEPTs, two classes of non-nucleoside human immunodeficiency virus type 1 (HIV-1) reverse transcriptase inhibitors (NNRTIs), which have been widely studied of late. All new derivatives were tested in MT-4 cells to explore their potential in vivo anti-HIV activity. Like other NNRTIs, they selectively inhibit HIV-1 but not HIV-2. The majority of test derivatives were found to have low potency and were sometimes more cytotoxic than zidovudine and emivirine (formerly MKC-442), used here as reference drugs. Uracil and cytosine derivatives bearing a sec-butoxy chain and a methyl-substituted benzenesulphonyl moiety were the most potent. Enzyme assays proved that these derivatives target RT. Structure-activity relationship studies established a correlation between the anti-HIV-1 activity and the meta substitution on the phenyl ring; furthermore, oxidation of sulphide to sulphone significantly increased the potency of certain derivatives.
authors.affiliation: Istituto Pasteur Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Università di Roma La Sapienza, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Costi
authors.forename: R
authors.initials: R
authors.lastname: Di Santo
authors.forename: M
authors.initials: M
authors.lastname: Artico
authors.forename: S
authors.initials: S
authors.lastname: Massa
authors.forename: A
authors.initials: A
authors.lastname: Lavecchia
authors.forename: T
authors.initials: T
authors.lastname: Marceddu
authors.forename: L
authors.initials: L
authors.lastname: Sanna
authors.forename: P
authors.initials: P
authors.lastname: La Colla
authors.forename: M E
authors.initials: ME
authors.lastname: Marongiu
mesh_terms: D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008826:Microbial Sensitivity Tests / Q000379:methods; D009705:Nucleosides / Q000737:chemistry; D011744:Pyrimidinones / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013440:Sulfides / Q000737:chemistry / Q000494:pharmacology
chemical_list: C116724:5-isopropyl-2-((methylthiomethyl)thio)-6-(benzyl)pyrimidin-4(1H)-one; D009705:Nucleosides; D011744:Pyrimidinones; D018894:Reverse Transcriptase Inhibitors; D013440:Sulfides