Pteridine moiety

Both sulfonamides and trimethoprim (not a sulfonamide) sequentially interfere with folic acid synthesis by bacteria. Folic acid functions as a coenzyme in the transfer of one-carbon units required for the synthesis of thymidine, purines, and some amino acids and consists of three components a pteridine moiety, PABA, and glutamate (Fig. 44.1). The sulfonamides, as structural analogues, competitively block PABA incorporation sulfonamides inhibit the enzyme dihydropteroate synthase, which is necessary for PABA to be incorporated into dihydropteroic acid, an intermediate compound in the formation of folinic acid. Since the sulfonamides reversibly block the synthesis of folic acid, they are bacteriostatic drugs. Humans cannot synthesize folic acid and must acquire it in the diet thus, the sulfonamides selectively inhibit microbial growth. 

Whereas the sulfonamides and sulfones inhibit the initial step whereby PABA and the pteridine moiety combine to form dihydropteroic acid (see Chapter 44), pyrimethamine and trimethoprim inhibit the conversion of dihydrofolic acid to tetrahydrofoUc acid, a reaction... 

The 2,6-diaminopyridine receptor sites in 16 are capable of binding guest molecules with a pteridine moiety. In the absence of metal cations 16 is closed ... 

The hydroxyl of Thr-113 forms a hydrogen bond to the carbox-ylate of Asp-27 and interacts with the 2-amino group of the pteridine moiety through a hydrogen-bonded water. Its replacement, in eDHFR, by Val decreases the binding of dihydrofolate 25-fold and causes a destabilization of the protein. In ADHFR, this residue is replaced by Ser, which, like Thr, can participate in the hydrogen bonding. 

The H NMR spectra of the pyrano[3,2-< ]pteridine (341) and its enantiomer derived from the phenylhydrazone of D-arabinose (343) show a time-dependent change due to the formation of an equilibrium involving the isomeric furo[3,2- ]-pteridines. Analogous results were obtained with 5,6-diamino-3-methyl-2-methylthio- and 5,6-diamino-2-methylthio-4(3//)-pyrimidone (342), respectively, leading in the latter case even to a separation of the two enantiomers (344) and (345) with respect to the chiral centers at the 6- and 7-position of the pteridine moiety (Equation (15)). 

Folic acid is a pteridine derivative (rings A and B constitute the pteridine heterocyclic system) synthesized by bacteria from GTP, p-aminobenzoic acid, and glutamic acid. Accordingly. the structure of folic acid is compased of three moieties the pteridine moiety derived from GTP. the p-aminobcnzoic acid moiety, and the glutamic acid moiety. (Antibacterial sulfonamides [see Chapter 8 compete with p-aminobenzoic acid and, thereby, interfere with bacterial folic acid synthesis.) Humans cannot synthesize folic acid. 

COMPOUNDS MODIFIED IN THE BRIDGE AND PTERIDINE MOIETY 5,10-Dideaza compounds... 

Fig. 26.17 Structure-based design of thymidylate synthase inhibitors, (a) The coenzyme 5,10-methylenete-trahydrofotate. (b) The classical antifolate CB3717. (c) Interactions of the pteridine moiety of CB3717 with active site residues Asp169 and Ala263 and with wat430, a bound water molecule. For explanation, see text. (Adapted, with permission, from Reich, S.H. and Webber, S.E. (1993) Perspect. Drug Dis. Des. 1 371-390. 1993 Escom Science Publishers B.V.)...

The guanidine analogues, in general, are not found to be active unless and imtil they get cyclized metabolically to a dihydro-s-triazine analogue having a close resemblance either to the pteridine moiety of folic acid or pyrimethamine as shown below ... 

The pyrimidine analogues have a close similarity to the pteridine moiety of dihydrofolic acid, and are directly responsible for its subsequent reduction to tetrahydrofolic acid by means of the enzyme dihydrofolate reductase. The site of action of pyrimidine analogues are exoerythrocytic and erythrocytic forms of P. falciparum, together with the exoeiythrocytic forms of P. vivax. A few examples of this category of antimalarials are described below ... 

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