DHFR inhibitors

Pneumocystis carinii DHFR inhibitor, Ki = 6.9 xM (about 30-foid seiectivity vs. human DHFR)... 

Plasmodium falciparum DHFR inhibitor, Ki = 0.9 jxM, Ki vs. different resistant strains = 0.6-2.1 xM... 

Streptococcus pneumoniae DHFR inhibitor, (R)-enantiomer, iCso = 9.8 niVI (S. pn. DHFR), iCgo = 2.8 nM (TMP-resistant S. pn. DHFR)... 

Protein synthesis and selective inhibition 5.3 DHFR inhibitors... 

Among these drugs, the dihydrofolate reductase (DHFR) inhibitors are used clinically with a certain amount of success. They belong to two major classes the classical antifolates which feature a polar amino-acid side chain terminus and those containing nonpolar side chains, called lipophilic or nonclassical anti-folates. 

Since hydrophobic interactions contribute largely to the DHFR-inhibitor binding, it was deemed interesting to apply ab initio methods to the description of aromatic-aromatic interactions. 

As the above examples have shown, the application of quantum-chemical calculations to the study of DHFR-inhibitor interaction can shed additional light on the problem. 

Iclaprim DHFR inhibitor 2008 2009 2010 cSSSIs caused by G+ bacteria including MRSA... 

Dihydrochalcones, 24 240—241 Dihydrofloriffone, 24 570 Dihydrofolate reductase (DHFR) inhibitors, 26 495-496... 

DHFR —> chicken DHFR) (benzylpyrimidines -> chicken DHFR) (inhibitors -> benzylpyrimidines) (3,4,5 OMe -> benzylpyrimidines) (equation -> benzylpyrimidines) (4-C1 4-Br)... 

The discovery of DHFR inhibitor NGD-157 demonstrates that ALIS is an efficient system for identifying novel, bioactive lead compounds from large combinatorial libraries. A single ALIS experiment containing over 2500 compounds is complete in under 10 min, allowing more than 250 000 compounds to... 

Fig. 3.10 Examples of isosteric binding competition. (A) ALIS-MS results for the titration of 5 pM Zap-70 by staurosporine in the presence of a 5 m concentration of its structural congener K252a and (B) titration of 5 pM DHFR with the known DHFR inhibitor trimethoprim in the presence of ligand NCD-157 at 5 pm concentration. Linear MS response ratios in these experiments are consistent with direct binding competition. (C) Compound structures.

Manganese dioxide can also be used for oxidations of activated alkyl groups, as demonstrated by the oxidation of the clinical dihydrofolate reductase (DHFR) inhibitor trimethoprim 586, to give the aryl ketone 587, without any need for protection of the two amino groups <2006BML4366>. 

Structure-activity correlations for the sulfa-DHFR inhibitors, derived on the basis of some 5000 compounds, have led to the deduction of the following regularities ... 

The other major class of antimalarials are the folate synthesis antagonists. There is a considerable difference in the drug sensitivity and affinity of dihydrofolate reductase enzyme (DHFR) between humans and the Plasmodium parasite. The parasite can therefore be eliminated successfully without excessive toxic effects to the human host. DHFR inhibitors block the reaction that transforms deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP) at the end of the pyrimidine-synthetic pathway. This reaction, a methylation, requires N °-methylene-tetrahydrofolate as a carbon carrier, which is oxidized to dihydrofolate. If the dihydrofolate cannot then be reduced back to tetrahydrofolate (THF), this essential step in DNA synthesis will come to a standstill. 

Using a guanidino group as the seed, output structures similar to several known DHFR inhibitors were generated, such as 74 which may be compared to trimethoprim (2). 

A group at Parke-Davis reported the preparation of 5-deazaAP (80a) in 1974 [74,75], This was the first synthesis of a member of this class of DHFR inhibitor. As shown in Scheme 3.16, the key intermediate, 2,4-diamino-5-deazapteridine-6-carbonitrile (79), was constructed in a straightforward manner in five steps from malononitrile. The use of chloroformamidine for the conversion of (78) to (79) proved to be less satisfactory than the (traditional) use of guanidine. 

Finally, Winchester, Zappone and Skinner have reported the synthesis of 7,8-dihydro-8-oxa-9-oxopteroic acid (190) as part of a programme to evaluate members of this class of heterocyclic compounds as DHFR inhibitors [112]. In their approach (Scheme 3.36 ), the key intermediate acid (187) was prepared from 2,5-diamino-4,6-dihydroxypyrimidine and ethyl bromopyruvate followed by saponification [113]. Owing to the extreme insolubility of (187) in most solvents, it was converted to the disodium salt (188) and treated with excess trifluoroacetic anhydride to yield the mixed anhydride (189) [114]. Coupling with p-aminobenzoic acid and careful base hydrolysis gave (190), albeit in low... 

As part of their programme to synthesize and evaluate potential DHFR inhibitors, Acharya and Hynes described a more convenient and economical route to 2-amino-4-hydroxy-6-bromomethylquinazoline (228), a key intermediate in their approaches to 5,8-dideazaFA analogues [ 126] (Scheme 3.41a). 

Winchester, Zappone and Skinner s synthesis of 7,8-dihydro-8-oxapteroic acid (190) represents the only example of this heterocyclic ring system incorporated into a precursor which could be elaborated to a FA analogue [ 112]. However, a recent report from Nair and co-workers describes this same ring system incorporated into potential DHFR inhibitors which have simultaneously been modified in the C-9,N-10 bridge region as well Scheme 3.63) [172]. 

Dihydrofolate reductase (DHFR), a classic target in antimicrobial and anticancer chemotherapy, has been shown to be a useful therapeutic target in plasmodium, toxoplasma, and eimeria species. Pyrimethamine is the prototypical DHFR inhibitor, exerting inhibitory effects in all three groups. However, pyrimethamine resistance in P falciparum has become widespread in recent years. This is largely attributable to specific point mutations in P falciparum DHFR that have rendered the enzyme less susceptible to the inhibitor. 

Of interest is a recently described yeast-based, nutrient-dependent viability screen for inhibitors of protozoal dihydrofolate reductase (DHFR) [43,44], Antiprotozoal activity of DHFR inhibitors is well known, and DHFR- yeast complemented with the DHFR gene derived from the malaria parasite P. falciparum have been used to characterize the molecular pharmacology of resistance to the antimalarial DHFR inhibitors pyrimethamine and cycloguanil [45,46], The subsequent development of a screen was based on the demonstration that the protozoal... 

Figure 3.13 Comparison of estimated and observed DHFR inhibitor activity values using a BCUT-based model (reprinted from [42] with permission, copyright 1999, American Chemical Society).

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