Antifolate agents: a patent review (2006 – 2010)

Abstract

Introduction For over 50 years, drugs targeting the folate pathway have significantly impacted disease treatment as anticancer, antimicrobial and immunomodulatory agents. The discovery of novel antifolate agents with improved properties and superior activities remains an attractive strategy, both in academia and the pharmaceutical industry. Areas covered This review surveys the patent literature from 2006–2010 for small molecule inhibitors of enzymatic targets in the folate biosynthetic pathway. Expert opinion The pursuit of antifolates as anticancer and antimicrobial agents continues to be an active area of research. New patent disclosures reveal novel antifolate scaffolds, antifolates with improved drug-like properties and new strategies to effectively target cancer cells. The continued use of high resolution structural information has guided the discovery of several compounds. Owing to the need for high levels of potency and selectivity, especially in targeting pathogenic species, the use of high resolution crystal structures remains an important tool to guide the design of novel antifolates. Interestingly, the patents disclosing novel compounds were ones where X-ray crystallography was an integral component of the design process. Finally, a variety of new structures have been reported that may play an important role in the future development of therapeutic antifolates.

Structural analysis of dihydrofolate reductases enables rationalization of antifolate binding affinities and suggests repurposing possibilities

“…The next four positions (18)(19)(20)(21) correspond to residues on the same loop as the PEKN insertion, connecting helix aII to strand b C . Positions 18 and 19 were seen to have positively charged residues and proline, respectively, in most species, whereas residues at positions 20 and 21 were seen to belong to more than two chemical types (Figs 3 and S1).…”

“…Positions 2-7 in the alignment belong to the Met20 loop (loop 1) of DHFR (E. coli DHFR: 9-24, human DHFR: [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]). This loop lies over the active site and regulates entry and exit of the substrate, product and Note: Only first author and year are provided for each reference.…”

Structure–activity relationship for enantiomers of potent inhibitors of B. anthracis dihydrofolate reductase

“…Aside from the scaffold described herein and also previously by Basilea Pharmaceutica Ltd. [6, 7], other anti-DHFR compounds under development include Iclaprim, being pursued by Acino Pharma [8], AR-709, pursued by Evolva [9], and 7-aryl-2,4-diaminoquinazolines, pursued by Trius Therapeutics [10]. A review of recent patent literature outlined antibacterial efforts targeting DHFR specifically for bacteria relevant to human health, including Staphylococcus aureus, Pneumocystis carinii and B. anthracis [11]. …”

One Substrate, Five Products: Reactions Catalyzed by the Dihydroneopterin Aldolase from Mycobacterium tuberculosis

“…1 It has been proposed that DHNA represents a promising new target for the development of antibacterials, underlying the importance of studying the catalytic and chemical mechanism of this enzyme in pathogenic bacteria such as Mycobacterium tuberculosis , the causative agent of tuberculosis. 2,3 DHNAs are interesting enzymes since they catalyze the cleavage of a carbon-carbon bond without the requirement of metals or cofactors, being considered a unique type of aldolase in which a substrate imbedded imine assists in catalysis.…”