Sulfonamides antimalarial

Category Antibiotic, sulfonamide Antimalarial Half-life 5-8 days... 

The first are competitors of PABA (p-aminobenzoic acid) and thus intermpt host de novo formation of the tetrahydrofoUc acid required for nucleic acid synthesis. Examples of dmgs that fall into this group are the sulfones and sulfonamides. The most weU-known of the sulfones is dapsone (70, 4,4 -diaminodiphenyl sulfone, DDS), whose toxicity has discouraged its use. Production of foHc acid, which consists of PABA, a pteridine unit, and glutamate, is disturbed by the substitution of a sulfonamide (stmcturally similar to PABA). The antimalarial sulfonamides include sulfadoxine (71, Fanasd [2447-57-6]) sulfadiazine (25), and sulfalene (72, sulfamethoxypyrazine [152-47-6] Kelfizina). Compounds of this group are rapidly absorbed but are cleared slowly. 

Clinical consequence hemolysis (breakdown of circulating red blood cells) from antimalarials, sulfonamides, nitrofurantoin, and other drugs. a-1 Antitrypsin deficiency, due to variants in this circulating plasma protein Frequency 1 /3000 Northern European Caucasians Clinical consequence predisposition to emphysema in early middle age, especially in cigarette smokers, due to failure to protect against trypsinlike enzymes in lung... 

Different antimalarials selectively kill the parasite s different developmental forms. The mechanism of action is known for some of them pyrimethamine and dapsone inhibit dihydrofolate reductase (p. 273), as does chlorguanide (proguanil) via its active metabolite. The sulfonamide sulfadoxine inhibits synthesis of dihydrofolic acid (p. 272). Chlo-roquine and quinine accumulate within the acidic vacuoles of blood schizonts and inhibit polymerization of heme, the latter substance being toxic for the schizonts. 

VI.a.2.3. Quinine alkaloids. The quinine alkaloids include quinine and quinidine. Quinidine, the dextrorotatory diastereoisomer of quinine, is mainly used for the parenteral treatment of cardiac arrhythmias but it can be an alternative antimalarial in regions where Plasmodium falciparum is resistant to both chloroquine and antifolate-sulfonamide combinations. 

In addition to its antimalarial effects, pyrimethamine is indicated (in combination with a sulfonamide) for the treatment of toxoplasmosis. The dosage required is 10 to 20 times higher than that employed in malarial infections. 

The answers are 484-k, 483-j. (Hardman, pp 1061—1062, 1682-1683.) Sulfonamides can cause acute hemolytic anemia. In some patients it may be related to a sensitization phenomenon, and in other patients the hemolysis is due to a glucose-6-phosphate dehydrogenase deficiency. Sulfamethoxazole alone or in combination with trimethoprim is used to treat UTIs. The sulfonamide sulfasalazine is employed in the treatment of ulcerative colitis. Dapsone, a drug that is used in the treatment of leprosy, and primaquine, an antimalarial agent, can produce hemolysis, particularly in patients with a glucose-6-phosphate dehydrogenase deficiency. 

The oldest example of the use of nonclassical isosteres involves the replacement of the carboxamide in foUc acid by sulfonamide, to give the sulfanilamides. Diaminopyrimidines, as antimalarial agents, are also based on folate isosterism, in addition to the exploitation of auxiliary binding sites on dihydrofolate reductase. This concept of nonclassical isosteres or bioisosteres — that is, moieties that do not have the same nnmber of atoms or identical electron structure — is really the classical structure modification approach. 

Trimethoprim is a pyrimidine derivative (diaminopyrimidine) related to antimalarial drug pyrimethamine, which selectively inhibits bacterial dihydrofolate reductase, necessary for the conversion of dihydrofolate to tetrahydrofolic acid. Sulfonamides act by inhibiting the incorporation of PABA into dihydrofolate by bacteria. A combination of... 

Some compounds are stored in the body in specific tissues. Such storage effectively removes the material from circulation and thus decreases the toxicity of the compound. Repeated doses of a toxic substance may be taken up and subsequently stored without apparent toxicity until the storage receptors become saturated then toxicity suddenly occurs. In some cases, the stored compound may be displaced from its storage receptor by another compound that has an affinity for the same receptor. Examples of this phenomenon are the displacement of antidiabetic sul-fonylureas by sulfonamides and the ability of antimalarial drugs such as quina-crine (atabrine) and primaquine to displace each other (Loomis, 1978). A special danger in such cases is that compounds may have escaped detoxifying metabolism while stored in the body, and that their toxicity may be potent and prolonged when released. 

A number of antibiotics in addition to the folate antagonists and sulfonamides are modestly active antimalarials. The antibiotics that are bacterial protein synthesis inhibitors appear to act against malaria parasites by inhibiting protein synthesis in a plasmodial prokaryote-like organelle, the apicoplast. None of the antibiotics should be used as single agents in the treatment of malaria because their action is much slower than that of standard antimalarials. 

Pyrimethamine may also be combined with other antimalarials such as artemisinin derivatives, but these regimens should only be used if the malarial parasites are not resistant to the specific drugs in the regimen.13 Pyrimethamine can also be combined with a sulfonamide drug such as dapsone, sulfadiazine, or sulfamethoxazole to treat protozoal infections that cause toxoplasmosis, or fungal infections that cause Pneumocystis pneumonia.These agents are administered orally. 

The gene encoding 7,8-dihydropteroate synthase was cloned from P falciparum and found to encode a bifunctional enzyme that includes the pyrophosphokinase at the amino terminal of the protein. Discrepancies were observed in the sequences of 7,8-dihydropteroate synthase portion of the genes from sulfadoxine-sensitive versus sulfadoxine-resistant P falciparum, thus confirming that this enzyme is the target for the antimalarial sulfonamide drugs. 

The pharmacologic properties of parasite 7,8-dihydropteroate synthases may differ from those of the bacterial enzymes. For instance, metachloridine and 2-ethoxy-p-aminobenzoate are both ineffective against sulfonamide-sensitive bacteria, but the former has antimalarial activity and the latter is effective against infection by the chicken parasite Eimeria acervulina both activities can be reversed by p-aminobenzoate. 

Caridha D, Kathcart AK, Jirage D, Waters NC (2010) Activity of substituted thiophene sulfonamides against malarial and mammalian cyclin dependent protein kinases. Bioorg Med Chem Lett 20(13) 3863-3867 Geyer JA, Keenan SM, Woodard CL et al (2009) Selective inhibition of Pfinrk, a Plasmodium falciparum CDK, by antimalarial l,3-diaryl-2-propenones. Bioorg Med Chem Lett 19(7) 1982-1985 Jirage D, Chen Y, Caridha D et al (2010) The malarial CDK Pfinrk and its effector PfMATl phosphorylate DNA replication proteins and co-localize in the nucleus. Mol Biochem Parasitol 172(1) 9-18... 

Sulfonamides maintain a significant role even today, because they are often used in combination with other antibacterials. For example, trimethyoprim, 35, has a diaminopyrimidine structure that has proved to be a highly selective, orally active, antibacterial, and antimalarial agent [6]. Trimethyoprim is combined to sulfamethoxazole, 36, for the treatment of bacterial respiratory tract infections and gastrointestinal infections [9]. 

Pyrimethamine is the most active antimalarial of the 2-4-diaminopyrimidines, its effect being due to inhibition of the conversion of foUc acid to its active form, folinic acid. It is also effective in toxoplasmosis. Its antiprotozoal and antimalarial activity is enhanced by the addition of sulfonamides. 

Just prior to 1950. great strides were made in anti-infective therapy. The sulfonamides and. sulfones (this chapter), more effective phenolic compounds such as hcxachlorophcnc. synthetic antimalarial compounds (Chapter 9). and a number of antibiotics (Chapter 10) wen introduced to the therapeutic armamentarium. 

Antibiotics, antiinflammatories, opiate analgesics Antibiotics, anticonvulsants, oral contraceptives Sulfonamides, gold, isoniazid, streptomycin quinicrine antimalarials (see Table 5)... 

The poultry industry employs the sulfonamides sulfaquinoxaline (114), also known as Diamprim, and sulfadimidine (115) for treatment of coccidiosis. The antimalarial pyrimethamine (116) (see Chapter 1) exhibits anti-coccidial properties, as does amprolium, APL, l-[(4-amino-2-propyl-5-pyrimidinyl)methyl]-2-methylpyridinium chloride hydrochloride (116a), a thiamine antagonist73. 

Clinically important, potentially hazardous interactions with amide-type anesthetics, antimalarials, cotrimoxazole, nitric compounds, sulfonamides... 

Jantschi, L. and Bolboaca, S. (2006) Molecular descriptors family on structure-activity relationships. 5. Antimalarial activity of 2,4-diamino-6-quinazoline sulfonamide derivates. Leonardo Journal of Sciences, 8, 77-88. 

Maier, J., and Riley, J. (1941). Inhibition of antimalarial action of sulfonamides by p-amino-benzoic add. Proc. Soc. Exp. Biol. Med. 152-154. 

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