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Chapter 4 : Antimicrobials to Antimalarials: Prontosil, Pyrimethamine, Proguanil, and Atovaquone
This chapter talks about the antimicrobials and antimalarials like Prontosil, pyrimethamine, proguanil, and atovaquone for the treatment of infectious diseases. The development of Prontosil began with the synthesis of a group of red azo dyes. The discovery of Prontosil opened up undreamed prospects for the treatment of infectious diseases. Prontosil treatment saved many people from the death sentence imposed by Streptococcus pyogenes. Almost at the same time that sulfanilamide was identified as the active principle of Prontosil, it was found to be an effective antimalarial in monkeys infected with P. knowlesi. The success of sulfa drugs encouraged the discovery of newer drugs, established research methods needed to find them, and created a business model for their development. The highest antimalarial activity was found in pyrimethamine, which resembled the antimalarial cycloguanil. Pyrimethamine inhibits the action of dihydrofolate reductase (DHFR) as it mimics DHF. The binding of pyrimethamine to DHFR relies on the structural differences between the host enzyme and that of the malaria parasite, and this is the basis for its selectivity and potency. Proguanil was inactive against the preblood (exoerythrocytic) stages of P. gallinaceum. Although proguanil on its own was inactive, antimalarial activity resulted from host metabolism to form the active molecule, when the serum from proguanil-treated monkeys inhibited the test tube growth of the preblood stages of P. gallinaceum. Proguanil emerged as the most promising partner for atovaquone. Atovaquone is also effective as a monotherapy against Pneumocystis jirovecii infections in AIDS patients.