ePrints

Nonclassical 2,4-diamino-5-aryl-6-ethylpyrimidine antifolates: Activity as inhibitors of dihydrofolate reductase from Pneumocystis carinii and Toxoplasma gondii and as antitumor agents

Lookup NU author(s): Professor Craig Robson, Professor Roger Griffin

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.

Abstract

Twelve novel 2,4-diamino-5-(4'-benzylamino)- and 2,4-diamino-5-[4'-(N- methylbenzylamino)-3'-nitrophenyl]-6-ethylpyrimidines bearing 4-substituents on the benzylamino or N-methylbenzylamino aryl ring were synthesized and evaluated as nonclassical inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase (DHFR). Compounds were prepared by reaction of 2,4-diamino-5-(4'-chloro-3'-nitrophenyl)-(8) or 2,4-diamino-5-(4'-fluoro-3'- nitrophenyl)-6-ethylpyrimidine (15) with the appropriate 4-substituted (CO2H, CO2Me, SO2NH2, dioxolan-2-yl, CHO, dimethyloxazolin-2-yl) benzylamine or N-methylbenzylamine derivative. Compounds 25-29 were synthesized from 2,4-diamino-5-{4'-[N-(4''-carboxybenzyl)amino]-3'- nitrophenyl}-6-ethylpyrimidine (10) and the corresponding amine (NH3, MeNH2, Me2NH, piperidine, diethyl L-glutamate) via isobutyl mixed anhydride coupling; hydrolysis of the diethyl L-glutamate 29 afforded the L-glutamate analogue 30. The compounds exhibited potent inhibitory activity against T. gondii (IC50 values 0.0018-0.14 μM) and rat liver (IC50 values 0.0029- 0.27 μM) DHFR, with a 4-substituent invariably enhancing binding to both enzymes relative to the unsubstituted benzoprim (5) or methylbenzoprim (6). Modest selectivity for T. gondii enzyme was observed with several analogues, whereas all of the compounds were relatively weak inhibitors of P. carinii DHFR and exhibited no selectivity. Selected analogues were evaluated for in vivo antitumor activity against the methotrexate-resistant M5076 murine reticulosarcoma, with 2,4-diamino-5-{4'-[N-[4''-(N'- methylcarbamoyl)benzyl]-N-methylamino]-3'-nitrophenyl}-6-ethylpyrimidine (14) (K(i) for rat liver DHFR = 0.000 35 ± 0.000 29 nM) combining significant antitumor activity with minimal toxicity.

Publication metadata

Author(s): Robson C, Meek M, Grunwaldt J, Lambert P, Queener S, Schmidt D, Griffin R

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 1997

Volume: 40

Issue: 19

Pages: 3040-3048

Print publication date: 01/01/1997

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

URL: http://dx.doi.org/10.1021/jm970055k

DOI: 10.1021/jm970055k

PubMed id: 9301666

Altmetrics

Funding

Share