Nonclassical 2,4-diamino-6-(aminomethyl)-5,6,7,8-tetrahydroquinazoline antifolates: synthesis and biological activities.
Twenty 6-substituted 2,4-diaminotetrahydroquinazolines were designed, synthesized, and biologically evaluated as novel nonclassical inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii and Toxoplasma gondii and as antitumor agents. The 6-substituents included substituted anilinomethyls, with alkoxy (OCH3, and OCH2CH3) and halogen (Cl and Br) moieties on the phenyl ring; an indolinomethyl; and 1-naphthylaminomethyls. The compounds were synthesized from a protected key intermediate 2,4-bis(acetamido)-5,6,7, 8-tetrahydroquinazoline-6-carboxaldehyde (26) by reductive amination with the appropriate amine. Compound 26 was obtained via a Diels--Alder reaction of 2-(trimethylsiloxy) -1,3-butadiene with acrolein to afford cyclohexanone-4-carboxaldehyde dimethyl acetal (23) after deprotection of the silyloxy group and protection of the aldehyde in a single step. Cyclocondensation of 23 with dicyandiamide followed by protection of the 2,4-diamino groups and deprotection of the 6-acetal gave 26. The compounds were significantly potent ((7-330) x 10(-9) M) and selective against T. gondii (versus rat liver DHFR). The most selective analogue against T. gondii DHFR was 2,4-diamino-6-[[(2',5'-dimethoxyphenyl) methylamino]methyl]-5,6,7,8-tetrahydroquinazoline (5) which showed exceptionally high inhibitory activity against the growth of T. gondii cells in culture (IC50 = 5.4 x 10(-8) M). Selected analogues were evaluated as inhibitors of the growth of tumor cells in culture. The most active analogues inhibited the growth of tumor cells at GI50 = 10(-8) M.
Gangjee
A
A
Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, USA.
Zaveri
N
N
Kothare
M
M
Queener
S F
SF
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D015195:Drug Design; D005493:Folic Acid Antagonists; D008099:Liver / Q000201:enzymology; D011010:Pneumocystis / Q000201:enzymology; D011799:Quinazolines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014122:Toxoplasma / Q000201:enzymology
D000970:Antineoplastic Agents; D005493:Folic Acid Antagonists; D011799:Quinazolines