Sulfonamides activity, antimalarial

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 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. 

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. 

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]. 

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. 

The activity and use of sulfonamides has been potentiated by addition of synergists that also inhibit bacterial enzymatic synthesis. The best known is trimethoprim 5-[(3,4,5-trimethoxyphenyl)methyl -2,4-pyrimidinediamine 47181 182 that binds dihydrofolic acid reductase. 43 and 47 are listed as antimalarial drugs183. 

A variety of representative sulfonamide derivatives, including acylated congeners and Schiff bases of sulfadiazine, sulfamethoxypyridazine, and metachloridine, has been prepared and tested for repository antimalarial activity [38]. Among them, 4 -(2-thiazolylsulfamoyl)acetanilide (XLIII), A -diacetyl-Ai-(2-pyrimidinyl)sulfanilamide (XLIV), 4,4 -bis(2-thiazolyl-sulfamoyl)thiocarbanilide (XLV), iVi-acetyl-iV -(6-methoxy-3-pyridazinyl)-sulfanilamide (XLVIa), N, A -diacetyl-iVi-(6-methoxy-3-pyridazinyl)sulfanil-... 

Barea C, Pabon A, Castillo D, Quiliano M, Galiano S, Perez-SUanes S, Monge A, Deharo E, Aldana I (2011) New salieylamide and sulfonamide derivatives of quinoxaline 1,4-di-iV-oxide with antileishmanial and antimalarial activities. Biooig Med Chem Lett 21(15) 4498-4502. doi 10.1016/j.bmel.2011.05.125... 

---