A New Class of Inhibitors of the AraC Family Virulence Regulator Vibrio Cholerae ToxT

Vibrio cholerae is responsible for the diarrheal disease cholera that infects millions of people worldwide. While vaccines protecting against cholera exist, and oral rehydration therapy is an effective treatment method, the disease will remain a global health threat until long-term solutions such as improved sanitation and access to clean water become widely available. Because of this, there is a pressing need for potent therapeutics that can either mitigate cholera symptoms, or act prophylactically to prevent the virulent effects of a cholera infection. Here we report the design, synthesis, and characterization of a set of compounds that bind and inhibit ToxT, the transcription factor that directly regulates the two primary V. cholerae virulence factors. Using the folded structure of the monounsaturated fatty acid observed in the X-ray structure of ToxT as a template, we designed ten novel compounds that inhibit the virulence cascade to a greater degree than any known inhibitor. Our findings provide a structural and functional basis for the development of viable antivirulence therapeutics that combat cholera and, potentially, other forms of bacterial pathogenic disease

Seroprevalence and distribution of arboviral infections among rural Kenyan adults: A cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Arthorpod-borne viruses (arboviruses) cause wide-spread morbidity in sub-Saharan Africa, but little research has documented the burden and distribution of these pathogens.</p> <p>Methods</p> <p>Using a population-based, cross-sectional study design, we administered a detailed questionnaire and used ELISA to test the blood of 1,141 healthy Kenyan adults from three districts for the presence of anti-viral Immunoglobulin G (IgG) antibodies to the following viruses: dengue (DENV), West Nile (WNV), yellow fever (YFV), Chikungunya (CHIKV), and Rift Valley fever (RVFV).</p> <p>Results</p> <p>Of these, 14.4% were positive for DENV, 9.5% were WNV positive, 9.2% were YFV positive, 34.0% were positive for CHIKV and 0.7% were RVFV positive. In total, 46.6% had antibodies to at least one of these arboviruses.</p> <p>Conclusions</p> <p>For all arboviruses, district of residence was strongly associated with seropositivity. Seroprevalence to YFV, DENV and WNV increased with age, while there was no correlation between age and seropositivity for CHIKV, suggesting that much of the seropositivity to CHIKV is due to sporadic epidemics. Paradoxically, literacy was associated with increased seropositivity of CHIKV and DENV.</p

Synthetic Studies on Furanosteroids: Construction of the Viridin Core Structure <i>via</i> Diels–Alder/<i>retro-</i>Diels–Alder and Vinylogous Mukaiyama Aldol-Type Reaction

The synthesis of the viridin class of furanosteroids core skeleton from the readily available 2,3-dihydro-4-hydroxyinden-1-one (<b>6</b>) is described. Our strategy was broken down into three parts: (1) Synthesis of functionalized alkyne oxazoles of type <b>5</b>; (2) intramolecular Diels–Alder/<i>retro</i>-Diels–Alder reaction of <b>5</b> followed by tautomerization and elaboration of R to give silylated furanonaphthols <b>4</b> bearing an aldehyde side chain; and (3) annulation of ring A by intramolecular vinylogous Mukaiyama aldol-type cyclization. Two major challenges were faced in the last step: (i) furanonaphthol derivatives bearing a β-hydroxyaldehyde functionality (R₁ = OH) suffered from dehydration to the <i>E</i>-enal, which is geometrically incapable of cyclization, and (ii) the functionality at C17 had a strong influence on the conversion of <b>4</b> to <b>3</b>, as exemplified by the failure of the free ketone (X = O) or its derivatives (X = H, OH; X = H, OAc) to cyclize. In the end, success was realized with the analogous C17-norketone (X = H, H)

Synthetic Studies on Furanosteroids: Construction of the Viridin Core Structure <i>via</i> Diels–Alder/<i>retro-</i>Diels–Alder and Vinylogous Mukaiyama Aldol-Type Reaction

The synthesis of the viridin class of furanosteroids core skeleton from the readily available 2,3-dihydro-4-hydroxyinden-1-one (<b>6</b>) is described. Our strategy was broken down into three parts: (1) Synthesis of functionalized alkyne oxazoles of type <b>5</b>; (2) intramolecular Diels–Alder/<i>retro</i>-Diels–Alder reaction of <b>5</b> followed by tautomerization and elaboration of R to give silylated furanonaphthols <b>4</b> bearing an aldehyde side chain; and (3) annulation of ring A by intramolecular vinylogous Mukaiyama aldol-type cyclization. Two major challenges were faced in the last step: (i) furanonaphthol derivatives bearing a β-hydroxyaldehyde functionality (R₁ = OH) suffered from dehydration to the <i>E</i>-enal, which is geometrically incapable of cyclization, and (ii) the functionality at C17 had a strong influence on the conversion of <b>4</b> to <b>3</b>, as exemplified by the failure of the free ketone (X = O) or its derivatives (X = H, OH; X = H, OAc) to cyclize. In the end, success was realized with the analogous C17-norketone (X = H, H)

Synthesis of a Dicyano Abietane, a Key Intermediate for the Anti-inflammatory Agent TBE-31

The synthesis of dicyano abietane <b>11</b>, a potential precursor to the biologically active tricyclic bis-cyano enone <b>6</b> (TBE-31), was accomplished in eight steps from epoxide <b>13</b>. The synthesis features a Lewis acid promoted stereoselective cyclization of epoxide <b>13</b> to generate the tricyclic ring system <b>12</b> in one step

Triple Benzannulation of Naphthalene via a 1,3,6-Naphthotriyne Synthetic Equivalent. Synthesis of Dibenz[<i>a</i>,<i>c</i>]anthracene

A new synthesis of dibenzo­[<i>a</i>,<i>c</i>]­anthracene (<b>4</b>) is described that features the generation, from tetrabromo-bis-triflate <b>1</b> and phenyllithium, of a 1,3,6-naphthotriyne (<b>2</b>) synthetic equivalent that is trapped with 3 equiv of furan to form Diels–Alder tris-adduct <b>3</b>. A subsequent two-step deoxygenation of <b>3</b> represents the first synthesis of dibenz­[<i>a</i>,<i>c</i>]­anthracene (<b>4</b>) that involves a tandem aryne Diels–Alder cycloaddition–deoxygenation strategy

Synthesis of a Masked 2,3-Diaminoindole

A three-step synthesis of masked 2,3-diaminoindole <b>1</b> from 2-iodo-3-nitro-1-(phenylsulfonyl)­indole (<b>2</b>) has been developed. Treatment of <b>1</b> with trifluoroacetic acid generates the unstable 2,3-diamino-1-(phenylsulfonyl)­indole (<b>3</b>), which can be trapped with α-dicarbonyl compounds to afford 5<i>H-</i>pyrazino­[2,3-<i>b</i>]­indoles <b>7</b>–<b>10</b>

Pyridyl analogs of 1-(2-cyano-3,12-dioxooleana-1,9(11)dien-28-oyl) imidazole

publication date: 2018-02-20; filing date: 2014-02-26Pyridyl analogs of 1-(2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl) imidazole and pharmaceutical compositions containing the same are provided. The present invention is a triterpenoid compound of Formula I, or a hydrate, isomer, prodrug or pharmaceutically acceptable salt thereof: wherein one or more of R, R or R is independently a substituted or unsubstituted aryl group, heteroaryl group, cycloalkyl group or heterocyclyl group, and the remaining R groups are hydrogen. The pyridyl analogs of CD-DO-1m 1 have been developed, which are more stable in human plasma and achieve a higher concentration in target tissues such as liver, pancreas, kidney and lungs

Human NCR3 gene variants rs2736191 and rs11575837 alter longitudinal risk for development of pediatric malaria episodes and severe malarial anemia

Abstract Background Plasmodium falciparum malaria is a leading cause of pediatric morbidity and mortality in holoendemic transmission areas. Severe malarial anemia [SMA, hemoglobin (Hb)  G and rs11575837:C > T) and their haplotypes. The prospective observational study was conducted over a 36 mos. follow-up period in a cohort of children (n = 1,515, aged 1.9–40 mos.) residing in a holoendemic P. falciparum transmission region, Siaya, Kenya. Results Poisson regression modeling, controlling for anemia-promoting covariates, revealed a significantly increased risk of malaria in carriers of the homozygous mutant allele genotype (TT) for rs11575837 after multiple test correction [Incidence rate ratio (IRR) = 1.540, 95% CI = 1.114–2.129, P = 0.009]. Increased risk of SMA was observed for rs2736191 in children who inherited the CG genotype (IRR = 1.269, 95% CI = 1.009–1.597, P = 0.041) and in the additive model (presence of 1 or 2 copies) (IRR = 1.198, 95% CI = 1.030–1.393, P = 0.019), but was not significant after multiple test correction. Modeling of the haplotypes revealed that the CC haplotype had a significant additive effect for protection against SMA (i.e., reduced risk for development of SMA) after multiple test correction (IRR = 0.823, 95% CI = 0.711–0.952, P = 0.009). Although increased susceptibility to SMA was present in carriers of the GC haplotype (IRR = 1.276, 95% CI = 1.030–1.581, P = 0.026) with an additive effect (IRR = 1.182, 95% CI = 1.018–1.372, P = 0.029), the results did not remain significant after multiple test correction. None of the NCR3 genotypes or haplotypes were associated with all-cause mortality. Conclusions Variation in NCR3 alters susceptibility to malaria and SMA during the acquisition of naturally-acquired malarial immunity. These results highlight the importance of NK cells in the innate immune response to malaria

CDDO-Me amino acid conjugates and methods of use

publication date: 2016-03-22; filing date: 2014-02-112-Cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid amino acid derivatives having antiinflammatory properties are provided. Pharmaceutical compositions and methods for preventing ior treating inflammation or a disease or condition mediated by inflammation are described