Dihydrofolate reductase inhibitor

sensitive to trimethoprim inhibition, but with a lower for dihydrofolate, which therefore competes with the drug more effectively  

sensitive to trimethoprim emd with a high for dihydrofolate, but induced by trimethoprim, thus increasing the eunount of enzyme available. 

Methotrexate is a potent inhibitor of dihydrofolate reductase, with an affinity 1,000-fold greater than that of dUiydrofolate. Chemotherapy consists of alternating periods of administration of methotrexate and folate (normally as 5-formyl-tetrahydrofolate, leucovorin) to replete the normal tissues and avoid induction of folate deficiency- so-called leucovorin rescue. As well as depleting tissue pools of tetrahydrofolate, methotrexate leads to the accumulation of relatively large amounts of 10-formyl-dihydrofolate, which is apotentinhibitor of both thymidylate synthetase and glycinamide ribotide transformylase, an intermediate step in purine nucleotide synthesis. It is likely that this, rather than simple depletion of tetrahydrofolate, is the basis of the cytotoxic action of methotrexate (Barametal., 1988). 

sensitive to trimethoprim and with a high Km for dUiydrofolate, hut induced hy trimethoprim, thus increasing the amount of enzyme avaUahle. 

Methotrexate is a potent inhibitor of dihydrofolate reductase, with an affinity 1,000-fold greater than that of dihydrofolate. Chemotherapy consists of alternating periods of administration of methotrexate and folate (normally as 

Methotrexate is also a substrate for conjugation with gluteunate (Section 

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Gerber, P. R., Mark, A. E., van Gunsteren, W. F. An approximate but efficient method to calculate free energy trends by computer simulation Application to dihydrofolate reductase-inhibitor complexes. J. Comp. Aid. Mol. Desgn 7 (1993) 305-323... 

T A and H Kalayeh 1991. Applications of Neural Networks in Quantitative Structure-Activity ationships of Dihydrofolate Reductase Inhibitors, journal of Medicinal Chemistry 34 2824-2836. ik M and R C Glen 1992. Applications of Rule-induction in the Derivation of Quantitative icture-Activity Relationships. Journal of Computer-Aided Molecular Design 6 349-383. 

The sulfa dmgs are stiH important as antimicrobials, although they have been replaced in many systemic infections by the natural and semisynthetic antibiotics. They are of great value in third world countries where problems of storage and lack of medical personnel make appropriate use of antibiotics difficult. They are especially useful in urinary tract infections, particularly the combination of sulfamethoxazole with trimethoprim. Their effectiveness has been enhanced by co-adniinistration with dihydrofolate reductase inhibitors, and the combination of sulfamethoxazole with trimethoprim is of value in treatment of a number of specific microbial infections. The introduction of this combination (cotrimoxazole) in the late 1960s (1973 in the United States) resulted in increased use of sulfonamides. 

Sulfonamides in combination with dihydrofolate reductase inhibitors are of continuing value. Pyrimethamine [58-14-0] (5) in combination with sulfonamides is employed for toxoplasmosis (7), and a trimethoprim (6)-sulfamethoxa2ole preparation is used not only for urinary tract infections but also for bmceUosis, cholera, and malaria. 

GM Crippen. Quantitative structure-activity relationships by distance geometry Systematic analysis of dihydrofolate reductase inhibitors. I Med Chem 23 599-606, 1980. 

TA Andrea, H Kalayeh. Applications of neural networks in quantitative structure-activity relationships of dihydrofolate reductase inhibitors. J Med Chem 34 2824-2836, 1991. 

Kuyper LF, Roth B, Baccanari DP, Ferone R, Beddell CR, Champness JN et al. Receptor-based design of dihydrofolate reductase inhibitors comparison of crys-tallographically determined enzyme binding with enzyme affinity in a series of carboxy-substituted trimethoprim analogues. J Med Chem 1982 25 1120-2... 

Rastelli G, Pacchioni S, Sirawaraporn W, Sirawaraporn R, Parenti MD, Ferrari AM. Docking and database screening reveal new classes of Plasmodium falciparum dihydrofolate reductase inhibitors. J Med Chem 2003 46 2834-45. 

Wyss PC, Gerber P, Hartman PG, Hubschwerlen C, Locher H, Marty HP, Stahl M. Novel dihydrofolate reductase inhibitors. Structure-based versus diversity-based library design and high-throughput synthesis and screening. J Med Chem 2003 46 2304-12. 

Ganjee and co-workers produced another series of potential dihydrofolate reductase inhibitors 84, initiating the cyclocondensation of pyrimidine 81 with ketone 82 in DMF at room temperature to give 83 in 53% yield <00JHC935>. 

DHFR - Dihydrofolate Reductase inhibitors - triazines, benzylpyrimidines, etc. 

Dihydrofolate reductase inhibitors from structure-based library design... 

The discovery of novel dihydrofolate reductase inhibitors by structure-based library design based on a 5-(dialkylamino)-2,4-diaminopyrimidine scaffold was reported by Wyss et al. [279] (cf Figure 4.5g). On the basis of a diaminopyrimidine core, a virtual... 

Rapidly dividing cells need an abundant supply of dTMP for DNA synthesis, and this creates a need for dihydrofolate reductase activity. Specific dihydrofolate reductase inhibitors have become especially useful as antibacterials, e.g. trimethoprim, and antimalarial drugs, e.g. pyrimethamine. 

Drugs that may interact with folic acid include aminosalicylic acid, oral contraceptives, dihydrofolate reductase inhibitors (eg, methotrexate, trimethoprim), sulfasalazine, hydantoins. 

HaU AJ, AchiUi L, Manesiotis P, Quaglia M, De Lorenzi E, SeUergren B. A substructure approach toward polymeric receptors targeting dihydrofolate reductase inhibitors. 2. Molecularly imprinted polymers against Z-L-glutamic acid showing affinity for larger molecules. J Org Chem 2003 68 9132-9135. 

Folate deficiency can be dietary, especially in the eiderly, due to increased demand like in pregnancy, or due to maiabsorption syndromes. Agents which can cause folic acid deficiency with long-term use include phenytoin, oral contraceptives, isoniazid and glucocorticosteroids. In rare instances the use of dihydrofolate reductase inhibitors like trimethoprim, methotrexate or pyrimethamine can contribute to the occurrence of folate deficiency. Folinic acid can circumvent the need for the inhibited dihydrofolate reductase. 

VI.a.2.2. Biguanides. Proguanil is a dihydrofolate reductase inhibitor. It is a slow acting blood schizonticide and not effective on its own. It has also a marked effect on the primary tissue stages of Plasmodium falciparum. It is used in combination with chloroquine for the prophylaxis of chloroquine-resistant Plasmodium falciparum. 

VI.a.2.4. Diaminopyrimidines. Pyrimethamine is a dihydrofolate reductase inhibitor, like the biguanides, and is structurally related to trimethoprim. It is seldom used alone. Pyrimethamine in fixed combinations with dapsone or sulfadoxine is used for treatment and prophylaxis of chloroquine-resistant falciparum malaria. The synergistic activities of pyrimethamine and sulfonamides are similar to those of trimethoprim/sulfonamide combinations. Resistant strains of Plasmodium falciparum have appeared world wide. Prophylaxis against falciparum... 

Used for malaria chemoprophylaxis and treatment the dihydrofolate reductase inhibitors do not cause pharmacological side-effects in the host. In the higher dose used for toxoplasmosis macrocytic anaemia and other adverse effects may occur. 

The combined use of sulfonamides or sulfones with dihydrofolate reductase inhibitors, such as trimethoprim Bactrim, Septra) or pyrimethamine Fansidar), s, a good example of the synergistic possibilities that exist in multiple-drug chemotherapy. This type of impairment of the parasite s metabolism is termed sequential blockade. Using drugs that inhibit at two different points in the same biochemical pathway produces parasite lethality at lower drug concentrations than are possible when either drug is used alone. 

Chloroguanide hydrochloride (Paludrine) is activated to a triazine metabolite, cycloguanil, which also interferes with parasite folic acid synthesis. It is a dihydrofolate reductase inhibitor that is used for the prophylaxis of malaria caused by all susceptible strains of plasmodia. Chloroguanide is rapidly absorbed from the gas-... 

Chemical Class Dihydrofolate reductase inhibitor (trimethoprim) sulfonamide derivative (sulfamethoxazole)... 

Administer as soon as possible following overdoses of dihydrofolate reductase inhibitors... 

Traditional Stille-type (49 + 50 -> 51 <998615>) and Heck-type couplings (52 S3 <99JHC145>) of halopyrimidines were also well represented. The latter reaction was utilized enroute to a new class of dihydrofolate reductase inhibitors 53. 

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