title: Synthesis and evaluation of 2-pyridinylpyrimidines as inhibitors of HIV-1 structural protein assembly.
abstract: In an effort to identify an HIV-1 capsid assembly inhibitor with improved solubility and potency, we synthesized two series of pyrimidine analogues based on our earlier lead compound N-(4-(ethoxycarbonyl)phenyl)-2-(pyridine-4-yl)quinazoline-4-amine. In vitro binding experiments showed that our series of 2-pyridine-4-ylpyrimidines had IC50 values higher than 28μM. Our series of 2-pyridine-3-ylpyrimidines exhibited IC50 values ranging from 3 to 60μM. The congeners with a fluoro substituent introduced at the 4-N-phenyl moiety, along with a methyl at C-6, represent potent HIV capsid assembly inhibitors binding to the C-terminal domain of the capsid protein.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences and IOCB Research Center, Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Milan
authors.initials: M
authors.lastname: Kožíšek
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences and IOCB Research Center, Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Ondřej
authors.initials: O
authors.lastname: Štěpánek
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences and IOCB Research Center, Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Kamil
authors.initials: K
authors.lastname: Parkan
authors.affiliation: Department of Organic Chemistry, Faculty of Science, Charles University, Hlavova 8, 128 43 Prague 2, Czech Republic.
authors.forename: Carlos
authors.initials: C
authors.lastname: Berenguer Albiñana
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences and IOCB Research Center, Flemingovo n. 2, 166 10 Prague 6, Czech Republic; Department of Infectious Diseases, Virology, University Hospital Heidelberg, Im Neuenheimer Feld 324, 691 20 Heidelberg, Germany.
authors.forename: Marcela
authors.initials: M
authors.lastname: Pávová
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences and IOCB Research Center, Flemingovo n. 2, 166 10 Prague 6, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Weber
authors.affiliation: Department of Infectious Diseases, Virology, University Hospital Heidelberg, Im Neuenheimer Feld 324, 691 20 Heidelberg, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Krӓusslich
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences and IOCB Research Center, Flemingovo n. 2, 166 10 Prague 6, Czech Republic; Department of Biochemistry, Faculty of Science, Charles University, Hlavova 8, 128 43 Prague 2, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Konvalinka
authors.affiliation: Department of Organic Chemistry, Faculty of Science, Charles University, Hlavova 8, 128 43 Prague 2, Czech Republic. Electronic address: macharaa@natur.cuni.cz.
authors.forename: Aleš
authors.initials: A
authors.lastname: Machara
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002213:Capsid / Q000737:chemistry / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D011743:Pyrimidines
keywords: Assay; Assembly; Capsid; Inhibition; Pyrimidine