528599-01-1Relevant articles and documents
New 2,4-Diamino-5-(2′,5′-substituted benzyl)pyrimidines as Potential Drugs against Opportunistic Infections of AIDS and Other Immune Disorders. Synthesis and Species-Dependent Antifolate Activity
Rosowsky, Andre,Forsch, Ronald A.,Sibley, Carol Hopkins,Inderlied, Clark B.,Queener, Sherry F.
, p. 1475 - 1486 (2004)
In a continuing effort to design small-molecule inhibitors of dihydrofolate reductase (DHFR) that combine the enzyme-binding selectivity of 2,4-diamino-5-(3′,4′,5′-trimethoxybenzyl)-pyrimidine (trimethoprim, TMP) with the potency of 2,4-diamino-5-methyl-6-(2′ ,5′-dimethoxybenzyl)pyrido[2,3-d]pyrimidine (piritrexim, PTX), seven previously undescribed 2,4-diamino-5-[2′-methoxy-5′-(substituted benzyl)]pyrimidines were synthesized in which the substituent at the 5′-position was a carboxyphenyl group linked to the benzyl moiety by a bridge of two or four atoms in length. The new analogues were all obtained from 2,4-diamino-5-(5′-iodo-2′-methoxybenzyl)pyrimidine via a Sonogashira reaction, followed, where appropriate, by catalytic hydrogenation. The new analogues were tested as inhibitors of DHFR from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), and Mycobacterium avium (Ma), three life-threatening pathogens often found in AIDS patients and individuals whose immune system is impaired as a result of treatment with immunosuppressive chemotherapy or radiation. The selectivity index (SI) of each compound was obtained by dividing its 50% inhibitory concentration (IC50) against Pc, Tg, or Ma DHFR by its IC50 against rat DHFR. 2,4-Diamino-[2′-methoxy-5′-(3-carboxyphenyl)-ethynylbenzyl] pyrimidine (28), with an IC50 of 23 nM and an SI of 28 in the Pc DHFR assay, had about the same potency as PTX and was 520 times more potent than TMP. As an inhibitor of Tg DHFR, 28 had an IC50 of 5.5 nM (510-fold lower than that of TMP and similar to that of PTX) and an SI value of 120 (2-fold better than TMP and vastly superior to PTX). Against Ma DHFR, 28 had IC50 and SI values of 1.5 nM and 430, respectively, compared with 300 nM and 610 for TMP. Although it had 2.5-fold lower potency than 28 against Ma DHFR (IC50 = 3.7 nM) and was substantially weaker against Pc and Tg DHFR, 2,4-diamino-[2′-methoxy-5′ -(4-carboxyphenyl)ethynylbenzyl]pyrimidine (29), with the carboxy group at the para rather than the meta position, displayed 2200-fold selectivity against the Ma enzyme and was the most selective 2,4-diamino-5-(5′-substituted benzyl)pyrimidine inhibitor of this enzyme we have encountered to date. Additional bioassay data for these compounds are also reported.
Further studies on 2,4-diamino-5-(2′,5′-disubstituted benzyl)pyrimidines as potent and selective inhibitors of dihydrofolate reductases from three major opportunistic pathogens of AIDS
Rosowsky, Andre,Forsch, Ronald A.,Queener, Sherry F.
, p. 1726 - 1736 (2007/10/03)
As part of an ongoing effort to discover novel small-molecule antifolates combining the enzyme-binding species selectivity of trimethoprim (TMP) with the potency of piritrexim (PTX), 10 previously unreported 2,4-diamino-5-(2′-methoxy-5′-substituted)benzylpyrimidines (2-11) containing a carboxyl group at the distal end of the 5′-substituent were synthesized and tested as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (Pc), Toxoplasma gondii (Tg), and Mycobacterium avium (Ma), three of the opportunistic pathogens frequently responsible for life-threatening illness in people with impaired immune systems as a result of HIV infection or immunosuppressive chemotherapy. The selectivity index of DHFR inhibition was evaluated by comparing the potency of each compound against the parasite enzymes with its potency against rat liver DHFR. 2,4-Diamino-5-[5′-(5-carboxy-1-pentynyl)-2′- methoxybenzyl]pyrimidine (3) inhibited Pc DHFR with a selectivity index of 79 and was 430 times more potent than TMP. 2,4-Diamino-5-[5′-(4-carboxy-1-butynyl)-2′-methoxybenzyl] pyrimidine (2), with one less carbon than 3 in the side chain, had a selectivity index of 910 against Ma DHFR and was 43 times more potent than TMP. 2,4-Diamino-5-[5′-(5-carboxypentyl)-2′-methoxybenzyl]pyri midine (6) had a selectivity index of 490 against Tg DHFR and was 320 times more potent than TMP. 2,4-Diamino-5-[5′-(6-carboxy-1-hexynyl)-2′-methoxybenzyl] pyrimidine (4), with one more carbon than 3, was less potent against all three of the parasite enzymes than either 3 or 6 and also had a lower selectivity index than 3 against the Pc enzyme. However, 4 was the only member of the series with a selectivity index of >300 against both Tg and Ma DHFR. Given that PTX is at least 10 times more potent against rat DHFR than against P. carinii or T. gondii DHFR and that the selectivity index of several of the compounds matches or exceeds that of TMP as well as PTX, our results suggest that it may be possible to develop clinically useful nonclassical antifolates that are both potent and selective against the major opportunistic pathogens of AIDS.
