Novel cis–trans enantiomeric conglomerates: triage and absolute configurations via anomalous X-ray scattering. A photochemical second order asymmetric transformation

Three tricyclic imides were prepared by a Diels–Alder reaction of 6-arylfulvenes and maleic anhydride, followed by treatment with $NH_3$. The exo isomers were found to exist as conglomerates when the aryl group was either p-tolyl or p-anisyl (although not phenyl). Triage of the p-tolyl racemate, followed by reaction with p-toluenesulfonyl chloride in $CH_2Cl_2/Et_3N$, led to the crystalline enantiopure Ntosylimides (these were also conglomerates). X-ray diffraction analysis of the N-tosylimides via the anomalous dispersion technique led to assignment of the absolute configurations (as either E or Z). The original p-tolyl imide enantiomers were found to racemize under UV irradiation in $CHCl_3$. Based on this, a possible second order asymmetric transformation under photochemical conditions was attempted, and indeed led to the isolation of crystalline imide with a small ee (\sim 15\%)

Biodegradation of methyl parathion and p-nitrophenol: evidence for the presence of a p-nitrophenol 2-hydroxylase in a Gram-negative Serratia sp. strain DS001

A soil bacterium capable of utilizing methyl parathion as sole carbon and energy source was isolated by selective enrichment on minimal medium containing methyl parathion. The strain was identified as belonging to the genus Serratia based on a phylogram constructed using the complete sequence of the 16S rRNA. Serratia sp. strain DS001 utilized methyl parathion, p-nitrophenol, 4-nitrocatechol, and 1,2,4-benzenetriol as sole carbon and energy sources but could not grow using hydroquinone as a source of carbon. p-Nitrophenol and dimethylthiophosphoric acid were found to be the major degradation products of methyl parathion. Growth on p-nitrophenol led to release of stoichiometric amounts of nitrite and to the formation of 4-nitrocatechol and benzenetriol. When these catabolic intermediates of p-nitrophenol were added to resting cells of Serratia sp. strain DS001 oxygen consumption was detected whereas no oxygen consumption was apparent when hydroquinone was added to the resting cells suggesting that it is not part of the p-nitrophenol degradation pathway. Key enzymes involved in degradation of methyl parathion and in conversion of p-nitrophenol to 4-nitrocatechol, namely parathion hydrolase and p-nitrophenol hydroxylase component “A” were detected in the proteomes of the methyl parathion and p-nitrophenol grown cultures, respectively. These studies report for the first time the existence of a p-nitrophenol hydroxylase component “A”, typically found in Gram-positive bacteria, in a Gram-negative strain of the genus Serratia

<i>Mycobacterium tuberculosis</i> IMPDH in Complexes with Substrates, Products and Antitubercular Compounds

Tuberculosis (TB) remains a worldwide problem and the need for new drugs is increasingly more urgent with the emergence of multidrug- and extensively-drug resistant TB. Inosine 5’-monophosphate dehydrogenase 2 (IMPDH2) from Mycobacterium tuberculosis (Mtb) is an attractive drug target. The enzyme catalyzes the conversion of inosine 5’-monophosphate into xanthosine 5’-monophosphate with the concomitant reduction of NAD+ to NADH. This reaction controls flux into the guanine nucleotide pool. We report seventeen selective IMPDH inhibitors with antitubercular activity. The crystal structures of a deletion mutant of MtbIMPDH2 in the apo form and in complex with the product XMP and substrate NAD+ are determined. We also report the structures of complexes with IMP and three structurally distinct inhibitors, including two with antitubercular activity. These structures will greatly facilitate the development of MtbIMPDH2-targeted antibiotics

Selective and Potent Urea Inhibitors of Cryptosporidium parvum Inosine 5′-Monophosphate Dehydrogenase

Cryptosporidium parvum and related species are zoonotic intracellular parasites of the intestine. Cryptosporidium is a leading cause of diarrhea in small children around the world. Infection can cause severe pathology in children and immunocompromised patients. This waterborne parasite is resistant to common methods of water treatment and therefore a prominent threat to drinking and recreation water even in countries with strong water safety systems. The drugs currently used to combat these organisms are ineffective. Genomic analysis revealed that the parasite relies solely on inosine-5′-monophosphate dehydrogenase (IMPDH) for the biosynthesis of guanine nucleotides. Herein, we report a selective urea-based inhibitor of C. parvum IMPDH (<i>Cp</i>IMPDH) identified by high-throughput screening. We performed a SAR study of these inhibitors with some analogues exhibiting high potency (IC₅₀ < 2 nM) against <i>Cp</i>IMPDH, excellent selectivity >1000-fold versus human IMPDH type 2 and good stability in mouse liver microsomes. A subset of inhibitors also displayed potent antiparasitic activity in a Toxoplasma gondii model

Optimization of Benzoxazole-Based Inhibitors of <i>Cryptosporidium parvum</i> Inosine 5′-Monophosphate Dehydrogenase

<i>Cryptosporidium parvum</i> is an enteric protozoan parasite that has emerged as a major cause of diarrhea, malnutrition, and gastroenteritis and poses a potential bioterrorism threat. <i>C. parvum</i> synthesizes guanine nucleotides from host adenosine in a streamlined pathway that relies on inosine 5′-monophosphate dehydrogenase (IMPDH). We have previously identified several parasite-selective <i>C. parvum</i> IMPDH (<i>Cp</i>IMPDH) inhibitors by high-throughput screening. In this paper, we report the structure–activity relationship (SAR) for a series of benzoxazole derivatives with many compounds demonstrating <i>Cp</i>IMPDH IC₅₀ values in the nanomolar range and >500-fold selectivity over human IMPDH (hIMPDH). Unlike previously reported <i>Cp</i>IMPDH inhibitors, these compounds are competitive inhibitors versus NAD⁺. The SAR study reveals that pyridine and other small heteroaromatic substituents are required at the 2-position of the benzoxazole for potent inhibitory activity. In addition, several other SAR conclusions are highlighted with regard to the benzoxazole and the amide portion of the inhibitor, including preferred stereochemistry. An X-ray crystal structure of a representative E·IMP·inhibitor complex is also presented. Overall, the secondary amine derivative <b>15a</b> demonstrated excellent <i>Cp</i>IMPDH inhibitory activity (IC₅₀ = 0.5 ± 0.1 nM) and moderate stability (<i>t</i>_1/2 = 44 min) in mouse liver microsomes. Compound <b>73</b>, the racemic version of <b>15a</b>, also displayed superb antiparasitic activity in a <i>Toxoplasma gondii</i> strain that relies on <i>Cp</i>IMPDH (EC₅₀ = 20 ± 20 nM), and selectivity versus a wild-type <i>T. gondii</i> strain (200-fold). No toxicity was observed (LD₅₀ > 50 μM) against a panel of four mammalian cells lines

Lionello Venturi e le polemiche sull’arte astratta in Italia alla metà del XX secolo.

Storia, critica dell'arte e politica nell'Italia del secondo dopoguerra

<i>Mycobacterium tuberculosis</i> IMPDH in Complexes with Substrates, Products and Antitubercular Compounds

<div><p>Tuberculosis (TB) remains a worldwide problem and the need for new drugs is increasingly more urgent with the emergence of multidrug- and extensively-drug resistant TB. Inosine 5’-monophosphate dehydrogenase 2 (IMPDH2) from <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) is an attractive drug target. The enzyme catalyzes the conversion of inosine 5’-monophosphate into xanthosine 5’-monophosphate with the concomitant reduction of NAD⁺ to NADH. This reaction controls flux into the guanine nucleotide pool. We report seventeen selective IMPDH inhibitors with antitubercular activity. The crystal structures of a deletion mutant of <i>Mtb</i>IMPDH2 in the apo form and in complex with the product XMP and substrate NAD⁺ are determined. We also report the structures of complexes with IMP and three structurally distinct inhibitors, including two with antitubercular activity. These structures will greatly facilitate the development of <i>Mtb</i>IMPDH2-targeted antibiotics.</p></div