5-Alkyl-2-alkylamino-6-(2,6-difluorophenylalkyl)-3,4-dihydropyrimidin-4(3H)-ones, a new series of potent, broad-spectrum non-nucleoside reverse transcriptase inhibitors belonging to the DABO family.
2-Alkylamino-6-[1-(2,6-difluorophenyl)alkyl]-3,4-dihydro-5-alkylpyrimidin-4(3H)-ones (F(2)-NH-DABOs) 4, 5 belonging to the dihydro-alkoxy-benzyl-oxopyrimidine (DABO) family and bearing different alkyl- and arylamino side chains at the C(2)-position of the pyrimidine ring were designed as active against wild type (wt) human immunodeficiency virus type 1 (HIV-1) and some relevant HIV-1 mutants. Biological evaluation indicated the importance of the further anchor point of compounds 4, 5 into the non-nucleoside binding site (NNBS): newly synthesized compounds were highly active against both wild type and the Y181C HIV-1 strains. In anti-wt HIV-1 assay the potency of amino derivatives did not depend on the size or shape of the C(2)-amino side chain, but it associated with the presence of one or two methyl groups (one at the pyrimidine C(5)-position and the other at the benzylic carbon), being thymine, alpha-methyluracil or alpha-methylthymine derivatives almost equally active in reducing wt HIV-1-induced cytopathogenicity in MT-4 cells. Against the Y181C mutant strain, 2,6-difluorobenzyl-alpha-methylthymine derivatives 4d, 5h'-n' showed the highest potency and selectivity among tested compounds, both a properly sized C(2)-NH side chain and the presence of two methyl groups (at C(5) and benzylic positions) being crucial for high antiviral action.
Mai
Antonello
A
Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Studi Farmaceutici, Università degli Studi di Roma La Sapienza, P. le A. Moro 5, I-00185 Roma, Italy. antonello.mai@uniroma.it
Artico
Marino
M
Ragno
Rino
R
Sbardella
Gianluca
G
Massa
Silvio
S
Musiu
Chiara
C
Mura
Massimo
M
Marturana
Flavia
F
Cadeddu
Alessandra
A
Maga
Giovanni
G
La Colla
Paolo
P
D000478:Alkylation; D000586:Amination; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000145:classification / Q000494:pharmacology*; D001593:Benzyl Compounds / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D005461:Fluorine / Q000737:chemistry; D054303:HIV Reverse Transcriptase / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D009705:Nucleosides / Q000737:chemistry; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000145:classification* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D019380:Anti-HIV Agents; D001593:Benzyl Compounds; D008024:Ligands; D009705:Nucleosides; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; D005461:Fluorine; D054303:HIV Reverse Transcriptase