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Ene-Reductases in Pharmaceutical Chemistry
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Phosphonates have wide applications in chemistry and biomedicine as they inhibit enzymes involved in several biological processes such as peptidoglycan and isoprenoid biosynthesis. Particularly interesting are derivatives of fosmidomycin and fosfomycin (Scheme 10.9), the latter being a rare epoxide containing antibiotic (Falagas et al., 2016). Schematic representation of fosfomycin, a rare epoxide-containing antibiotic.
Biosynthetic Pathway of Artemisinin
Published in Tariq Aftab, M. Naeem, M. Masroor, A. Khan, Artemisia annua, 2017
These two compartmentalized pathways of terpene biosynthesis communicate with each other to regulate metabolic intermediate availability. There are no absolute restrictions on the compartmentalization of intermediates in the pathways, and the degree of separation depends on the species and physiological conditions (Hampel et al., 2005). In A. annua, both the MVA and MEP seem to play a role in artemisinin production. When the cytosolic MVA is disrupted by inhibiting HMGR with mevinolin, artemisinin levels drop by about 80%. When DXR in the MEP is inhibited by fosmidomycin, artemisinin levels drop by about 70%. Use of both inhibitors leads to negligible artemisinin production in A. annua, suggesting that the two pathways interlink with each other to enhance this production (Towler and Weathers, 2007).
Terpenes and Terpenoids
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
William J. Rea, Kalpana D. Patel
Isoprene is made through the methylerythritol 4-phosphate pathway (MEP pathway, also called the nonmevalonate pathway) in the chloroplasts of plants. One of the two end products of the MEP pathway, DMADP, is catalyzed by the inside isoprene synthase to form isoprene. Therefore, an inhibitor that blocks the MEP pathway, such as fosmidomycin, also block isoprene formation. Isoprene emission increases dramatically with temperature and maximizes at around 40°C (Figure 8.1).
Can Plasmodium’s tricks for enhancing its transmission be turned against the parasite? New hopes for vector control
Published in Pathogens and Global Health, 2019
S. Noushin Emami, Melika Hajkazemian, Raimondas Mozūraitis
Isoprenoids are widespread molecules and are necessary for all living organisms [58]. These molecules are involved in a vast spectrum of metabolic processes and serve as building blocks in the synthesis of various compounds such as cholesterol, steroid hormones and vitamins [59]. Animals, fungi and a few bacteria produce isoprenoids through a biosynthetic route called mevalonate pathway. By contrast, eubacteria, plastid-containing eukaryotes and most bacteria use an alternate metabolic route, the non-mevalonate or methylerythritol phosphate (MEP) pathway. Plants use both pathways, the chloroplast-localized MEP pathway that is used for biosynthesis of the terpene volatiles that contributs their characteristic flavors and fragrances [60]. MEP pathway is used by parasitic apicomplaxan protozoa, including Plasmodium (reviewed in [61]). The MEP pathway is one of the recognizable pathways in malaria parasite apicoplast and this pathway might have evolved due to its lower energy consumption (reviewed in [45]). Due to its non-host specificity, biochemical reactions of MEP pathway have been favored as a highlighted target for novel antiparasitic drugs in human host. For example, fosmidomycin and its derivative, FR-900098 have an antibiotic activity that targets DOXP reductoisomerase and inhibits the growth of asexual stage of malaria parasite [62]. Parasites lost their apicoplast after non-antifolate antibiotic treatments such as doxycycline. Interestingly, parasite growth (asexual stage) is rescued upon simultaneous supplementation with the central isoprenoid precursor, isopentenyl pyrophosphate (IPP) [63].
AQ-13 - an investigational antimalarial drug
Published in Expert Opinion on Investigational Drugs, 2019
Juliana Boex Mengue, Jana Held, Andrea Kreidenweiss
Malaria chemotherapies in the pipeline are either based on previously registered drug combinations and are now developed as new formulations particularly for pediatrics (e.g. dihydroartemisinin-piperaquine dispersible) or are combined to new partner drugs (e.g. artemisinin-piperaquine). Naphthoquine is a 4-aminoquinoline derivative that is co-formulated to artemisinin and is a promising new ACT with the potential for single dose administration [26]. Interestingly, several molecules with novel mechanisms of action are investigated as well as 4-aminoquinoline derivatives. Ferroquine is a CQ derivative with a ferrocene molecule at its lateral chain that is also active against CQ resistant parasites. Ferroquine is tested in an ongoing phase 2b study (NCT02497612) in combination with OZ439, a next-generation artemisinin, for single dose treatment of uncomplicated P. falciparum malaria [27,28]. Fosmidomycin, an antibiotic combined to a second antibiotic clindamycin or to piperaquine, is developed as a new non-ACT for uncomplicated malaria [30,31]. Molecules with new chemical scaffolds include KAF156 (combined to lumefantrine), KAE609, DSM256, and MMV048. They are all in phase 2 trials and are developed towards a medicine for single-exposure, radical cure [32].
The treatment of melioidosis: is there a role for repurposed drugs? A proposal and review
Published in Expert Review of Anti-infective Therapy, 2019
Thomas R Laws, Adam W. Taylor, Paul Russell, Diane Williamson
A multitude of small compounds have been considered as putative inhibitors of the Type III secretion system, and these are summarized below from two review articles [28,65]. However, to our knowledge, none of these compounds are in clinical use and would therefore require significant development prior to use in melioidosis patients. The only inhibitor of type III secretion that has been used in clinical trials is an antibody fragment (KB001-A) found to interact with the type III secretion system of P. aeruginosa [66]. Releases in the public media, however, revealed reported commercial concerns with regard to success criteria, and it has since been shelved. Variants of thiazolidinones (a class of small molecule that has been very useful in drug discovery [67]) have been used clinically for unrelated purposes (rosiglitazone and pioglitazone, which are both insulin sensitizers); however, it is clear that the structure of these molecules can to be optimized for effect in inhibiting type III secretion systems in both bacteria from the genus Salmonella and Yersinia [68]. With regard to compounds that can inhibit type II fatty acid synthesis, Anthranilic acid has been used clinically previously [69] and has chemistry associated with other clinically used products. Indole-3-carbinol, which is similar (SB418001), has also been used clinically [70]. Also dithiolethiones have been studied in some detail, more so in the form of Oltipraz, which was tolerated in humans with some adverse effects [71]. 4-aminopyridime (or famridine) bears similarity to the aminopyridine that targets bacteria [72] and has been shown to be tolerated in a clinical trial [73]. The easiest fatty acid synthesis inhibitor to repurpose might be Isoniazid, which is already in clinical use for the treatment of Mycobacterium infection. Another drug that is worthy of investigation is fosmidomycin. This drug is currently used as an antimalarial and targets DXP reductoisomerase, a critical enzyme in the nonmevalonate pathway. This drug also targets this pathway in at least some Gram negative bacteria [74].