The natural antibiotic fosmidomycin acts via inhibition of 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR), an essential enzyme in the non-mevalonate pathway of isoprenoid biosynthesis. Fosmidomycin is active on Mycobacterium tuberculosis DXR (MtDXR), but it lacks antibacterial activity probably because of poor uptake. α-Aryl substituted fosmidomycin analogues have more favorable physicochemical properties and are also more active in inhibiting malaria parasite growth. We have solved crystal structures of MtDXR in complex with 3,4-dichlorophenyl substituted fosmidomycin analogues; these show important differences compared to our previously described forsmidomycin–DXR complex. Our best inhibitor has an IC50 = 0.15 μM on MtDXR but still lacked activity in a mycobacterial growth assay (MIC > 32 μg/mL). The combined results, however, provide insights into how DXR accommodates the new inhibitors and serve as an excellent starting point for the design of other novel and more potent inhibitors, particularly against pathogens where uptake is less of a problem, such as the malaria parasite.

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Intermolecular tandem copper-catalyzed O-arylation-oxidative acylation (cross dehydrogenative coupling-CDC) has been developed under air as an oxidant. The reaction between 2,4-dihydro-3H-pyrazol-3-ones and ortho-halo aryl carboxaldehydes furnished the corresponding chromone fused pyrazoles, in a straightforward manner. The synthetic utility of the presented tandem catalysis has been demonstrated with the synthesis of an A-subtype selective adenosine receptor antagonist in only two steps.

The antimalarial compound fosmidomycin targets DXR, the enzyme that catalyzes the first committed step in the MEP pathway producing the essential isoprenoid precursors, isopentenyl diphosphate and dimethylallyl diphosphate. The MEP pathway is used by a number of pathogens, including Mycobacterium tuberculosis and apicomplexan parasites, and differs from the classical mevalonate pathway that is essential in humans. Using a structure-based approach, we designed a number of analogues of fosmidomycin, including a series that are substituted in both the Cα and the hydroxamate positions. The latter proved to be a stable framework for the design of inhibitors that extend from the polar and cramped (and so not easily druggable) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 substrate-binding site and can, for the first time, bridge the substrate and cofactor binding sites.A number of these compounds are more potent than fosmidomycin in terms of killing Plasmodium falciparum in an in vitro assay; the best has an IC 50 of 40 nM. IntroductionFosmidomycin (1) and its acetyl derivative, , are natural product antibiotics with activity against a number of important pathogens. 1,2 They work by blocking the pathway for biosynthesis of isopentenyl diphosphate and dimethylallyl diphosphate that proceeds via the intermediate 2-C-methyl-D-erythritol 4-phosphate (MEP). This MEP pathway is used in Gramnegative and some Gram-positive bacteria, as well as in plant chloroplasts, algae and apicomplexan protozoa. 3 The enzymes involved are essential to the organisms possessing them, yet completely absent in humans, and they have therefore received considerable attention as potential targets for antimicrobial drug discovery. Fosmidomycin and 2 act by inhibiting the second (and first committed) step in the pathway, 4, 5 in which 1-deoxy-D-xylulose 5-phosphate (DXP) is converted to MEP by the enzyme 1-deoxy-D-xylulose-5-phosphate reductoisomerase (DXR, also called IspC). A number of major pathogens are dependent upon the MEP pathway, although not all are sensitive to fosmidomycin and its analogues. For example, while both 1 and 2 inhibit the DXRs of the protozoan Plasmodium falciparum (PfDXR) 6 and Mycobacterium tuberculosis (MtDXR), 7-10 the Plasmodium species are sensitive to these antibiotics in vitro and in vivo, 6 but the mycobacteria are not. 11 The use of fosmidomycin as a single-drug treatment for P. falciparum malaria has been hampered by low bioavailability, rapid clearance from the parasite and recrudescent infection, 12 although the compound has been used more successfully in combination with clindamycin. 13 Failure to obtain biological activity against mycobacteria appears to result from poor uptake. 11Page 3 of 36 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34...

Selective formation of esters from primary alcohols or formic acid from carbon dioxide was achieved in the presence of phosphine-pyridone containing ruthenium catalysts.

A unique intramolecular vinylogous Michael addition leading to the synthesis of heterocycles has been disclosed. Base-promoted one-pot sequential O-allylation of o-hydroxy-cinnamates or -cinnamonitrile or -chalcones with γ-bromocrotonates followed by an intramolecular conjugate addition of vinylogous Michael donors resulted in the formation of highly substituted benzofuran derivatives in good to excellent yields. The intramolecular event followed by two [1,3]-H shifts leading to aromatization appears to be the key to the success of this unprecedented transformation.

A novel organocatalytic approach, harnessing the unique reactivities of N-heterocyclic carbenes (NHCs), has been revealed for the construction of indoles. The NHC-catalysed atom economical synthesis of a wide range of 2-substituted indole-3-acetic acid derivatives is displayed. Strategic application of the developed method was demonstrated for a short synthesis of a cyclin-dependent kinase (CDK) inhibitor: paullone.

An efficient and mild one-pot, gold-catalyzed intramolecular cyclization of N-propargylic β-enaminones has been achieved for the generation of 1,4-oxazepine derivatives. This synthetic transformation tolerates a range of substituted N-propargylic β-enaminones in moderate to good yields.