Towards Species-specific Antifolates

Abstract

Dihydrofolate reductase (DHFR) plays an essential role in cellular biochemistry and has been a well-recognized drug target for over fifty years. Antifolate inhibitors of DHFR, including clinically used therapeutics such as methotrexate, trimethoprim, and pyrimethamine have been successful as anticancer, antibacterial, antifungal and antiparasitic agents. As resistant strains of these microorganisms evolve and as new disease threats arise, the need for new antifolates that are potent and specific for infectious organisms becomes more pressing. Several new antifolates have been reported over the past decade; many of these are potent against a particular species of DHFR, but achieving the goal of potency and selectivity has proven to be more difficult. This review will describe recent advances in attaining species selectivity in developing new antifolates. Specifically, advances in developing inhibitors against Pneumocystis jirovecii and Plasmodium falciparum, the causative agents in pneumocystis pneumonia and malaria, respectively, will be presented.

Design, Synthesis, and Biological Evaluation of Classical and Nonclassical 2-Amino-4-oxo-5-substituted-6-methylpyrrolo[3,2-d]pyrimidines as Dual Thymidylate Synthase and Dihydrofolate Reductase Inhibitors

“…This silica gel plug was loaded on a dry silica gel column (2 cm × 15 cm) and flash-chromatographed initially with n-hexane (200 mL) and then sequentially with 500 mL of 5% ethyl acetate in n-hexane, 500 mL of 10% ethyl acetate in n-hexane, and 500 mL of 15% ethyl acetate in n-hexane. Fractions containing the desired product (TLC) were pooled and evaporated to afford 6.74 g (80%) of 20 as an off-white solid: mp 50-52 °C; 1 …”

“…1,2 Inhibitors of folate-dependent enzymes in cancer, microbial, and protozoan cells provide compounds that have found clinical utility as antitumor, antimicrobial, and antiprotozoal agents. 3,4 Thymidylate synthase (TS a ),which catalyzes the reductive methylation of deoxyuridylate (dUMP) to deoxythymidylate (dTMP), has been of particular interest.…”

Kinetic and Structural Analysis for Potent Antifolate Inhibition of Pneumocystis jirovecii, Pneumocystis carinii, and Human Dihydrofolate Reductases and Their Active-Site Variants

“…Failure of therapy or prophylaxis with TMP is common, but attempts to link these failures to variants of P. jirovecii dihydrofolate reductase (pjDHFR) that lead to alternative forms of the enzyme have been inconclusive (7,8). To date, most structural and drug design efforts have focused on the DHFR from Pneumocystis carinii (pcDHFR), the organism originally isolated from rat lungs (9)(10)(11)(12). Recent observations show differences in drug sensitivity between pc-and pjDHFR that suggest designed optimization of antifolates would more selectively target pjDHFR (13).…”

Ultrasound Mediated One-Pot, Three Component Synthesis, Docking and ADME Prediction of Novel 5-Amino-2-(4-chlorophenyl)-7-Substituted Phenyl-8,8a-dihydro-7H-(1,3,4)thiadiazolo(3,2-α)pyrimidine-6-carbonitrile Derivatives as Anticancer Agents

“…Folate metabolism is considered as an important target for the development of new anticancer agents due to its role in the biosynthesis of nucleic acid precursors [5,6]. The inhibition of folate dependent enzymes such as thymidylate synthase (TS), which catalyzes the reductive methylation of deoxyuridylate (dUMP) to thymidylate (dTMP) has also been recognized as an interesting target for drug discovery [7,8].…”