Antiprotozoal enzyme inhibitors

Replacing the electrophilic epoxy ketone moiety in TPX by a reversible zinc chelator such as a hydroxamic acid was carried out by Yoshida et al. (Fig. 6) [51]. This modification led to a low nanomolar reversible inhibitor of the HDACl enzyme. Several other cyclic tetrapeptides containing the epoxyketone feature, such as chlamydocin, were converted into their hydroxamic acid coimterparts as well [52]. Additionally, the introduction of reversed hydroxamic acids (-N(OH)COR, with R = H or Me) onto the structure of Cyl-1 was reported to give potent HDAC inhibitors as illustrated in Fig. 6 [53]. Generally, the most potent inhibitors were the examples with R = H and m = 2. Apicidin, a cychc peptide more remotely related to TPX, exhibits potent antiprotozoal activity via HDAC inhibition in parasites [54]. 

Folate analogs such as trimethoprim have potent antibacterial and antiprotozoal activity. Trimethoprim binds lO -fold less tightly to mammalian dihydrofolate reductase than it does to reductases of susceptible microorganisms. Small differences in the active-site clefts of these enzymes account for its highly selective antimicrobial action. The combination of trimethoprim and sulfamethoxazole (an inhibitor of folate synthesis) is widely used to treat infections. 

DIHYDROFOLATE REDUCTASE INHIBITORS have as a target the enzyme dihydrofolate reductase, and are known as folate antagonists. These include anttcancer agents ( antimetabolites ) such as methotrexate, antibacterial AGENTS such as trimethoprim, and the antiprotozoals pyrimethamine and proguanil (which are used to treat malaria). Folate is required for synthesis of purine nucleotides, which in turn are essential for DNA synthesis and cell division. In mammals it is necessary to convert body folates, through two separate enzyme-catalysed reduction... 

It was shown that the IPC synthase was induced upon differentiation,47 providing an important target for antiprotozoal therapy, since no equivalent mammalian enzyme is known. In this respect, biosynthesis of radioactive IPC by metabolic labeling of T. cruzi epimastigotes,66 trypomastigotes,69 and amastigotes47 could be used to study the action of potential inhibitors. Properties of the IPC synthase have been described,70 but in contrast to earlier results,47 the authors report no inhibition of the enzyme by aureobasidin. Elucidation of the structure of the T. cruzi enzyme would clarify its analogy with the yeast enzyme. 

Dlhydrofplate Reductase Inhibitors - This enzyme (DHFF) reduces dlhydrofollc acid (] ) to tetrahydrofollc acid - an essential cofactor with important roles In DNA synthesis and cell growth. DHFR can be widely different In structure in different cells, and Inhibitors which exploit these differences Include clinically useful antibacterial, antiprotozoal, Immunosuppressant and antlneoplastlc drugs. A vast amount of synthetic analog work in this field has been done, much of it by Baker.68 Hansch and co-workers used data from several groups and QSAR techniques to "map" receptor space for DHFR from rat liver, from... 

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