Antifungal enzyme inhibitors

Cyclosporin is metabolised by the hepatic cytochrome P-450 enzyme system, and enzyme induction by phenobarbital, phenytoin, carbamazepine, or rifampicin will drastically increase the clearance of cyclosporin. Concurrent administration of these drugs has caused rejection of transplanted organs. Conversely, the use of enzyme inhibitors, such as erythromycin or the azole antifungal agents, e.g. ketoconazole, will increase the blood concentrations of cyclosporin leading to an increased risk of toxic side effects. 

Bhandari et al. (56) modified a hit structure derived from the primary screening of various libraries (>300,000 compounds) on the zinc metalloenzyme phosphomannose isomerase from the yeast Candida albicans (CaPMI) to find enzyme inhibitors as jxitential antifungal agents. During primary screening only a 1296-member SP dipeptide pool library (Lll, Fig. 9.16) showed activity on the enzyme. Its deconvolution and analytical characterization led to the discovery of a by-product, derived from incomplete coupling, that showed activity on the enzyme. This compound (9.21, Fig. 9.16) showed a weak inhibitory activity on CaPMI (ICso = 40 xM) and was selected for further chemical profiling. 

ANTIFUNGAL, ANTIMICROBIAL and ANTIINFLAMMATORY activity, and to be a powerful cytotoxic agent (functioning by DNA intercalation and uncoupling of oxidative phosphorylation). It is an ENZYME INHIBITOR (alanine aminotransferase and human plasma diamine oxidase). It shows antiplaque activity, and has been used in toothpastes and oral rinses. Causes temporary change in intraocular pressure. Sanomigran pizotifen. 

Remember some of those drugs that are key enzyme inducers (e.g. phenytoin, barbiturates, rifampicin, etc) or enzyme inhibitors (e.g. azole antifungals, HIV-protease inhibitors, erythromycin, SSRIs). 

Ebelaetones. Enzyme inhibitors with /3-lactone structure from cultures of Streptomyces aburaviensis. E. A C20H34O4, Mr 338.49, needles, mp. 86 °C, [a] - 221 ° (CHjOH)) and . B C2 H3 04,Mr352.51,needles,nip. 77 °C, Icc]d -203° (CH3OH) inhibit membrane-bound esterases, lipases, and aminopeptidases of animal cells as well as cutinases of fungal cells (antifungal activity). 

Concomitant administration with cytochrome P450 hepatic enzyme inhibitors, e.g. macrobde antibiotics, antifungal agents, verapamil, cimetidine, ciprofloxacin, enoxacin, fluvoxamine, amiodarone... 

Secondary metabolites are employed as antitumor agents, immunosuppressive agents, enzyme inhibitors, antiparasitic agents, etc. Many of these products were first discovered as antibiotics that failed in their commercial development as such, although a few successfid secondary metabolites appear to have no antibiotic activity. The recently increased development of resistance to older antibacterial and antifungal dru is being met with the use or clinical testing of older undemtilized or previously nondeveloped narrow-spectrum antibacterial products. 

Addition of Phosphorus Nucleophiles to Imines As the Pudovik and the Abramov reactions constitute phosphorus analogs of the aldol reaction, there is also a phosphorus equivalent for the Mannich reaction, namely, the Kabachnik-Fields reaction (see Scheme 47.7). In this process, phosphorus nucleophiles add to imines to produce a-aminophosphonate derivatives, which can be considered amino acid analogs. These compounds by themselves, or when incorporated into short peptides, find applications as enzyme inhibitors or as antibacterial and antifungal agents. However, in only a few instances were optically pure derivatives prepared for biological and pharmaceutical applications. Examples include the synthesis of antibiotic ala-fosfalin 82, penicillopepsin 83, and HIV protease... 

Thiourea compounds have been observed to inhibit human immunodeficiency virus (HIV) reverse transcriptase, a viral enzyme that is responsible for the reverse transcription of the retroviral RNA to proviral DNA. Phenethylthiazoylthiourea (PETT) compounds were discovered as potent inhibitors of HIV type 1 and display certain structure-activity relationships among various substituents in their structure.199 207 Furthermore, thiourea derivatives have been found to be potent and selective viral inhibitors, antifungal and antibacterial compounds.208 215... 

We first applied Tethering to thymidylate synthase (TS). This enzyme converts de-oxyuridine monophosphate (dUMP) to thymidine monophosphate (dTMP), an activity essential for DNA synthesis. The cancer drug 5-fluorouracil irreversibly inhibits TS, and a selective inhibitor of a non-human form of the enzyme could yield a new antibiotic or antifungal drug [23]. 

The impact of small molecules on the acetylation status of histones has attracted the interest of the medicinal chemistry community for almost a decade now. Nevertheless, the fast and reversible increase in cellular histone acetylation in the presence of -butyrate was already recognized in 1977 by Riggs et al. (Fig. 3) [30]. Two years later, it was proven that n-butyrate, among some related and less active small linear aliphatic carboxylates, was a noncompetitive inhibitor of histone deacetylating enzymes [31-34]. More than ten years after the initial interest in -butyrate, Yoshida et al. showed that trichostatin A (TSA, Fig. 3), originally reported as an antifungal agent [35],... 

P-450 system Monitoring of circulating cyclosporine levels and appropriate dosage adjustment are essential when drugs that affect hepatic microsomal enzymes, particularly the cytochrome P-450 3A enzymes, are used concomitantly (eg, HIV protease inhibitors, anticonvulsants, azole antifungals). 

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