Expanding Benzoxazole-Based Inosine 5?-Monophosphate Dehydrogenase (IMPDH) Inhibitor Structure–Activity As Potential Antituberculosis Agents

New drugs and molecular targets are urgently needed to address the emergence and spread of drug-resistant tuberculosis. Mycobacterium tuberculosis (Mtb) inosine 5?-monophosphate dehydrogenase 2 (MtbIMPDH2) is a promising yet controversial potential target. The inhibition of MtbIMPDH2 blocks the biosynthesis of guanine nucleotides, but high concentrations of guanine can potentially rescue the bacteria. Herein we describe an expansion of the structure–activity relationship (SAR) for the benzoxazole series of MtbIMPDH2 inhibitors and demonstrate that minimum inhibitory concentrations (MIC) of ?1 ?M can be achieved. The antibacterial activity of the most promising compound, 17b (Q151), is derived from the inhibition of MtbIMPDH2 as demonstrated by conditional knockdown and resistant strains. Importantly, guanine does not change the MIC of 17b, alleviating the concern that guanine salvage can protect Mtb in vivo. These findings suggest that MtbIMPDH2 is a vulnerable target for tuberculosis

Diastereoselective Synthesis of 1‑Deoxygalactonojirimycin, 1‑Deoxyaltronojirimycin, and <i>N</i>‑Boc-(2<i>S</i>,3<i>S</i>)‑3-Hydroxypipecolic Acid via Proline Catalyzed α‑Aminoxylation of Aldehydes

An efficient synthesis of deoxygalactonojirimycin and deoxyaltronojirimycin through the use of proline catalyzed asymmetric α-aminoxylation of a higher homologue of Garner’s aldehyde, derived from l-aspartic acid, is reported. The method is also used for a highly diastereoselective synthesis of the <i>N</i>-Boc derivative of (2<i>S</i>,3<i>S</i>)-3-hydroxypipecolic acid. The configuration of the proline catalyst used for the asymmetric aminoxylation step ultimately controls the absolute configuration of three adjacent stereogenic centers in the final products

Fungally Derived Isoquinoline Demonstrates Inducer-Specific Tau Aggregation Inhibition

The microtubule-associated protein tau promotes the stabilization of the axonal cytoskeleton in neurons. In several neurodegenerative diseases, such as Alzheimer’s disease, tau has been found to dissociate from microtubules, leading to the formation of pathological aggregates that display an amyloid fibril-like structure. Recent structural studies have shown that the tau filaments isolated from different neurodegenerative disorders have structurally distinct fibril cores that are specific to the disease. These “strains” of tau fibrils appear to propagate between neurons in a prion-like fashion that maintains their initial template structure. In addition, the strains isolated from diseased tissue appear to have structures that are different from those made by the most commonly used in vitro modeling inducer molecule, heparin. The structural differences among strains in different diseases and in vitro-induced tau fibrils may contribute to recent failures in clinical trials of compounds designed to target tau pathology. This study identifies an isoquinoline compound (ANTC-15) isolated from the fungus Aspergillus nidulans that can both inhibit filaments induced by arachidonic acid (ARA) and disassemble preformed ARA fibrils. When compared to a tau aggregation inhibitor currently in clinical trials (LMTX, LMTM, or TRx0237), ANTC-15 and LMTX were found to have opposing inducer-specific activities against ARA and heparin in vitro-induced tau filaments. These findings may help explain the disappointing results in translating potent preclinical inhibitor candidates to successful clinical treatments

Controlling Growth to One Dimension in Nanoislands of Ferrocene-Sugar Derivatives

Ferrocenyl-Alkyl-Protected Sugar (Fc-Sug) and Ferrocenyl-Oxo-Alkyl-Protected Sugar (Fc-Oxo-Sug) were deposited on the basal plane of Highly Oriented Pyrolytic Graphite (HOPG) using a drop-casting method. Ultrathin films of these molecules were investigated using Atomic Force Microscopy to understand the growth at low coverage. Both molecules are forming highly ordered one-dimensional molecular islands, which are growing from a dimer building block. The dimer and interdimer interactions (along the length of islands) are stabilized by −C₂O···H–C hydrogen bonding. Unlike for Fc-Sug, the islands of Fc-Oxo-Sug are extended to tens of micrometers, and the growth is only limited by terrace edges or other islands on the surface. This exceptional growth of islands is understood in terms of an additional −CO···H–C– hydrogen bonding leading to stronger interdimer interactions along the length of the islands compared to Fc-Sug

Expanding Benzoxazole-Based Inosine 5′-Monophosphate Dehydrogenase (IMPDH) Inhibitor Structure–Activity As Potential Antituberculosis Agents

New drugs and molecular targets are urgently needed to address the emergence and spread of drug-resistant tuberculosis. <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) inosine 5′-monophosphate dehydrogenase 2 (<i>Mtb</i>IMPDH2) is a promising yet controversial potential target. The inhibition of <i>Mtb</i>IMPDH2 blocks the biosynthesis of guanine nucleotides, but high concentrations of guanine can potentially rescue the bacteria. Herein we describe an expansion of the structure–activity relationship (SAR) for the benzoxazole series of <i>Mtb</i>IMPDH2 inhibitors and demonstrate that minimum inhibitory concentrations (MIC) of ≤1 μM can be achieved. The antibacterial activity of the most promising compound, <b>17b</b> (<b>Q151</b>), is derived from the inhibition of <i>Mtb</i>IMPDH2 as demonstrated by conditional knockdown and resistant strains. Importantly, guanine does not change the MIC of <b>17b</b>, alleviating the concern that guanine salvage can protect <i>Mtb</i> in vivo. These findings suggest that <i>Mtb</i>IMPDH2 is a vulnerable target for tuberculosis

Expanding Benzoxazole-Based Inosine 5′-Monophosphate Dehydrogenase (IMPDH) Inhibitor Structure–Activity As Potential Antituberculosis Agents

New drugs and molecular targets are urgently needed to address the emergence and spread of drug-resistant tuberculosis. <i>Mycobacterium tuberculosis</i> (<i>Mtb</i>) inosine 5′-monophosphate dehydrogenase 2 (<i>Mtb</i>IMPDH2) is a promising yet controversial potential target. The inhibition of <i>Mtb</i>IMPDH2 blocks the biosynthesis of guanine nucleotides, but high concentrations of guanine can potentially rescue the bacteria. Herein we describe an expansion of the structure–activity relationship (SAR) for the benzoxazole series of <i>Mtb</i>IMPDH2 inhibitors and demonstrate that minimum inhibitory concentrations (MIC) of ≤1 μM can be achieved. The antibacterial activity of the most promising compound, <b>17b</b> (<b>Q151</b>), is derived from the inhibition of <i>Mtb</i>IMPDH2 as demonstrated by conditional knockdown and resistant strains. Importantly, guanine does not change the MIC of <b>17b</b>, alleviating the concern that guanine salvage can protect <i>Mtb</i> in vivo. These findings suggest that <i>Mtb</i>IMPDH2 is a vulnerable target for tuberculosis