Halo Analogs Research Articles

Therapeutic Potential of Iridoid Derivatives: Patent Review

Iridoids belong to a family of monoterpenoids comprising the cyclopentan[c]-pyran system; this class of compounds offers a wide range of biological effects, namely antileishmanial, anticancer, antiplasmodial, and anti-inflammatory potency. To date, a large number of biologically active iridoid derivatives have been reported from various plant families, including Rubiaceae, Plantaginaceae, Scrophulariaceae, and Verbenaceae. Furthermore, iridoids have the potential to form conjugates with other anticancer, antidiabetic, antileishmanial, and antimalarial drugs which synergistically have the potential to increase their effects. Additionally, future research should focus on the synthesis of halo analogs as well as preparing homo dimers or heterodimers of iridoids, since these might quite conceivably possess an increased bioactivity.

Piperidin-1-ylamidomethyltellurium derivatives: Synthesis and solid state structures

Oxidative insertion of low valent tellurium, Te(0) and Te(II), into the CBr bond of α-bromoacetylpiperidine proceeds readily under mild conditions and provides a direct synthetic route to stable, crystalline piperidin-1-ylamidomethyltellurium(IV) dibromides, (C5H10NCOCH2)2TeBr2, 1b and (C5H10NCOCH2)ArTeBr2 (Ar=2,4,6-Me3C6H2, 2b; 1-C10H7, 3b; 4-MeC6H4, 4b). While the bisulfite reduction of 1b affords a yellow coloured telluroether, (C5H10NCOCH2)2Te, 1 as an oil, that of the unsymmetrical diorganotellurium dibromides, (C5H10NCOCH2)ArTeBr2 leads to the isolation of the respective diarylditellurides, ArTeTeAr. The symmetrical telluroether, 1 adds dihalogens oxidatively to give piperidin-1-ylamidomethyltellurium(IV) dihalides, (C5H10NCOCH2)2TeX2 (X=Cl, 1a; Br, 1b and I, 1c;). All the new piperidin-1-ylamidomethyltellurium derivatives have been characterized by elemental and 1H, 13C, 125Te NMR spectral analyses. Single-crystal X-ray diffraction data for 1b and 1c indicated a butterfly molecular shape for the two halo analogues in which the six-member heterocyclic rings in the organic ligands retain the chair conformation of the independent piperidine molecule. The piperidin-1-yl appended organic ligand invariably results in the amido O atom being involved in an intramolecular Te O secondary bonding interaction and acts as a small-bite (C, O) chelating agent, at least in the solid state. Steric congestion around the six-coordinate Te(IV) atom and the partial positive charge on N owing to the resonating character of the NCO amido group prevents these atoms from participating in the intermolecular associative forces. Instead, the weak CH⋯O and CH⋯Br interactions take centre-stage in the solid state self-assembly.

Haloarene Derivatives of Carbamazepine with Reduced Bioactivation Liabilities: 2-Monohalo and 2,8-Dihalo Derivatives

The anticonvulsant carbamazepine 1 is associated with adverse drug reactions (ADRs), including hepatotoxicity; oxidative metabolism of 1 has been implicated in the pathogenesis of the ADRs. We report the synthesis and evaluation of 2-monohalo and 2,8-dihalo analogues of 1 that were intended to minimize reactive metabolite formation via arene oxidation and 10,11-epoxidation. Halo analogues were obtained either by rearrangement of halogenated N-arylindoles or from specifically halogenated iminodibenzyl derivatives. In rat hepatocytes, none of the analogues underwent oxidative dehalogenation or glutathione adduction. Some formation of the 10,11-epoxide still occurred, but aromatic hydroxylation was not seen with the exception of 2-fluoro, which allowed minor monohydroxylation. Complete inhibition of aromatic hydroxylation required at least monochlorination or difluorination of 1. In human liver microsomes, difluoro analogue 5b underwent 10,11-epoxidation but gave no arene oxidation.

Engineering inhibitors highly selective for the S1 sites of Ser190 trypsin-like serine protease drug targets

Background: Involved or implicated in a wide spectrum of diseases, trypsin-like serine proteases comprise well studied drug targets and anti-targets that can be subdivided into two major classes. In one class there is a serine at position 190 at the S1 site, as in urokinase type plasminogen activator (urokinase or uPA) and factor VIIa, and in the other there is an alanine at 190, as in tissue type plasminogen activator (tPA) and factor Xa. A hydrogen bond unique to Ser190 protease–arylamidine complexes between Oγ Ser190 and the inhibitor amidine confers an intrinsic preference for such inhibitors toward Ser190 proteases over Ala190 counterparts. Results: Based on the structural differences between the S1 sites of Ser190 and Ala190 protease–arylamidine complexes, we amplified the selectivity of amidine inhibitors toward uPA and against tPA, by factors as high as 220-fold, by incorporating a halo group ortho to the amidine of a lead inhibitor scaffold. Comparison of K i values of such halo-substituted and parent inhibitors toward a panel of Ser190 and Ala190 proteases demonstrates pronounced selectivity of the halo analogs for Ser190 proteases over Ala190 counterparts. Crystal structures of Ser190 proteases, uPA and trypsin, and of an Ala190 counterpart, thrombin, bound by a set of ortho (halo, amidino) aryl inhibitors and of non-halo parents reveal the structural basis of the exquisite selectivity and validate the design principle. Conclusions: Remarkable selectivity enhancements of exceptionally small inhibitors are achieved toward the uPA target over the highly similar tPA anti-target through a single atom substitution on an otherwise relatively non-selective scaffold. Overall selectivities for uPA over tPA as high as 980-fold at physiological pH were realized. The increase in selectivity results from the displacement of a single bound water molecule common to the S1 site of both the uPA target and the tPA anti-target because of the ensuing deficit in hydrogen bonding of the arylamidine inhibitor when bound in the Ala190 protease anti-target.

Cyclization reactions of ?-tosyloxy-1-alkynyl- and ?-tosyloxy-1-alkenylborates and their ?-halo analogues

The reaction of trialkylboranes with ω-tosyloxy-1-lithio-1-alkynes can induce transfer of an alkyl group from the boron atom to the alkynyl carbon atom with concomitant formation of four- through six-membered carbocycles via intramolecular displacement of the ω-tosyloxy group. The stereoselectivity of the reaction, however, is low (anti/syn≃1.6–1.7). The corresponding reaction of ω-halo- or ω-tosyloxy-1-alkenylborates also gives exocyclic alkenes via 1,2-migration-cyclization followed by dehydroboration. In the cases of cyclopropanation, cyclopropylcarbinyl-to-homopropargyl rearrangement rather than dehydroboration takes place. Diphenylzirconocene reacts similarly with 6-lithio-5-hexynyl tosylate to give phenylmethylenecyclopentane in 45% yield. On the other hand, attempts to induce a similar migration with phenyl derivatives of Y, V, Cr, and Mn have led to < 5–10% yields of the same cyclization product.

Resolved and unresolved crystallographic disorder between cyano-.eta.3-[hydrotris(3-tert-butylpyrazolyl)borato]zinc and the halo analogs.

Crystallographic disorder between structurally inequivalent groups has been investigated by X-ray diffraction studies. By use of a technique in which a crystal is doped with an impurity, the disorder at a single site was varied in a controlled fashion. Specifically, single crystals of composition {η 3 -HB(3-Bu t pz) 3 }Zn(CN) x X 1-x (3-Bu t pz=3-C 3 N 2 H 2 Bu t ; X=Cl, Br, I; 0≤x≤1) were obtained by cocrystallization of {η 3 -HB(3-Bu t pz) 2 }ZnCN

5'-Alkyl-substituted analogs of 5'-methylthioadenosine as trypanocides

5'-Deoxy-5'-(methylthio)adenosine (MTA) is a by-product of polyamine metabolism and is phosphoryolytically cleaved to adenine and 5-deoxy-5-(methylthio)ribose-1-phosphate (MTR-1-P) by MTA phosphorylase. In eukaryotes, adenine is subsequently salvaged and converted to nucleotides, while MTR-1-P is converted to methionine. We examined 5'-deoxy-5'-substituted analogs of MTA for trypanocidal activity in vitro and in vivo. 5'-Deoxy-5'-(hydroxyethyl)thioadenosine (HETA) and its 5'-bromo,5'-chloro and 5'-fluoro derivatives were cleaved by extracts of the African trypanosome Trypanosoma brucei brucei (Km for MTA, 11.5 microM; Km for HETA, 13.2 microM) in a phosphate-dependent reaction. HETA and the three halo analogs were 50% inhibitory to growth at 0.5 to 5.0 microM in vitro. Inhibition of growth was reversible by exogenous methionine and 2-keto-4-methylthiobutyric acid, an intermediate in methionine synthesis from MTR-1-P. HETA was selected for further study in vivo. When administered by miniosmotic pump (25 to 150 mg/kg/day for 7 days) to mice infected with T. brucei brucei, HETA effected 70 to 90% cure rates. Results of this study indicate that these analogs of MTA are converted to trypanocidal MTR-1-P analogs and that this approach deserves further consideration in the development of novel chemotherapy of trypanosomiasis.

Synthesis and herbicidal activity of the halo analogs of pyoluteorin

The synthesis of some halo analogues of pyoluteorin [2,3-dichloro-5-(2',6'-dihydroxybenzoyl)-1H-pyrrole] through the use of a Friedel-Crafts aroylation of pyrrole with 2,6-dimethoxybenzoyl chloride, followed by halogenation and demethylation with boron tribromide, is described. Stepwise bromination of the intermediate 2-(2',6'-dimethoxybenzoyl)pyrrole yielded the di-, tri-, and tetrabromo derivatives. Similarly, chlorination gave the dichloro and the trichloro derivatives whereas iodination with even an excess of iodine gave only the monoiodo derivative. (...)

Halo lipids. V. Synthesis, nuclear magnetic resonance spectra and cytostatic properties of halo analogues of alkyllysophospholipids

A series of fluorine- and chlorine-containing analogues of alkyllysophospholipids has been synthesised as potential antimetabolites of phospholipids. These compounds include various structural isomers of racemic long-chain alkyldeoxyhaloglycerophosphocholines and N, N-dimethylethanolamines, alkyldeoxyhaloglycerophosphoric acids, and alkyl esters. 1H- and 19F-NMR spectroscopic data are presented and analysed. Alkyldeoxyhaloglycerophosphocholines were found to exhibit a strong inhibitory effect on the proliferation of Ehrlich ascites carcinoma cells in vitro.

Effects of Halo Analogs of Glycerol 3-Phosphate and Dihydroxyacetone Phosphate upon Escherichia coli

The fluoro and chloro analogs of glycerol 3-phosphate inhibit the growth of Escherichia coli and affect bacterial enzymes involved in lipid synthesis.

Kinetic studies of the reaction between dihalodicarbonylrhodate(I) anions and 2-aminopyridine

The kinetic behavior of the reaction between dihalodicarbonylrhodate(I) anions, [RhX 2(CO) 2] −1, where X = Cl, Br, and the chelating agent 2-aminopyridine was investigated spectrophotometrically. The reaction for both halo analogues was found to obey third order kinetics, first order in the complex anion and second order in the 2-aminopyridine concentrations. The third order rate constants for the chloro and bromo complex anions had the values, at 25°C, of 779 and 156 l 2 mol −2 min −1, respectively, and the corresponding activation energies were 3.00 and 5.50 Kcal mol −1. A mechanism is proposed to account for these observations.

Alanine racemase of Pseudomonas: Observations on subtrate and inhibitor specificity

Systematic studies with purified alanine racemase and a number of substrate analogs permit the generalization that effective competitive inhibition is limited to 2- and 3-carbon compounds. A free α-amino group was not necessary for relatively tight binding; compounds lacking an amino group, or with an α-amino group acylated even by a bulky substituent, were bound as tightly as alanine. Substitution at the α-carbon of alanine (i.e., replacement of the α-H) eliminated binding, while substitution at the β-carbon generally reduced binding. Of several inhibitory compounds tested for substrate activity by H exchange with 3H 2O, only glycine appeared active. Covalent binding to the enzyme by halo analogs was not demonstrated.