Multigram-scale chemoenzymatic synthesis of diverse aminopolycarboxylic acids as potential metallo-ß-lactamase inhibitors.

Toxin A, a precursor to naturally occurring aspergillomarasmine A, aspergillomarasmine B, lycomarasmine and related aminopolycarboxylic acids, was synthesized as the desired (2S,2'S)-diastereomer on a multigram-scale (>99% conversion, 82% isolated yield, dr > 95 : 5) from commercially available starting materials using the enzyme ethylenediamine-N,N'-disuccinic acid lyase. A single-step protection route of this chiral synthon was developed to aid N-sulfonylation/-alkylation and reductive amination at the terminal primary amine for easy derivatization, followed by global deprotection to give the corresponding toxin A derivatives, including lycomarasmine, in moderate to good yields (23-66%) and with high stereopurity (dr > 95 : 5). Furthermore, a chemoenzymatic route was developed to introduce a click handle on toxin A (yield 72%, dr > 95 : 5) and its cyclized congener for further analogue design. Finally, a chemoenzymatic route towards the synthesis of photocaged aspergillomarasmine B (yield 8%, dr > 95 : 5) was established, prompting further steps into smart prodrug design and precision delivery. These new synthetic methodologies have the prospective of facilitating research into the finding of more selective and potent metallo-ß-lactamase (MBL) inhibitors, which are urgently needed to combat MBL-based infections.

Impact of HDAC inhibitors on macrophage polarization to enhance innate immunity against infections.

Innate immunity plays an important role in host defense against pathogenic infections. It involves macrophage polarization into either the pro-inflammatory M1 or the anti-inflammatory M2 phenotype, influencing immune stimulation or suppression, respectively. Epigenetic changes during immune reactions contribute to long-term innate immunity imprinting on macrophage polarization. It is becoming increasingly evident that epigenetic modulators, such as histone deacetylase (HDAC) inhibitors (HDACi), enable the enhancement of innate immunity by tailoring macrophage polarization in response to immune stressors. In this review, we summarize current literature on the impact of HDACi and other epigenetic modulators on the functioning of macrophages during diseases that have a strong immune component, such as infections. Depending on the disease context and the chosen therapeutic intervention, HDAC1, HDAC2, HDAC3, HDAC6, or HDAC8 are particularly important in influencing macrophage polarization towards either M1 or M2 phenotypes. We anticipate that therapeutic strategies based on HDAC epigenetic mechanisms will provide a unique approach to boost immunity against disease challenges, including resistant infections.

Tailored photoenzymatic systems for selective reduction of aliphatic and aromatic nitro compounds fueled by light.

The selective enzymatic reduction of nitroaliphatic and nitroaromatic compounds to aliphatic amines and amino-, azoxy- and azo-aromatics, respectively, remains a persisting challenge for biocatalysis. Here we demonstrate the light-powered, selective photoenzymatic synthesis of aliphatic amines and amino-, azoxy- and azo-aromatics from the corresponding nitro compounds. The nitroreductase from Bacillus amyloliquefaciens, in synergy with a photocatalytic system based on chlorophyll, promotes selective conversions of electronically-diverse nitroarenes into a series of aromatic amino, azoxy and azo products with excellent yield (up to 97%). The exploitation of an alternative nitroreductase from Enterobacter cloacae enables the tailoring of a photoenzymatic system for the challenging synthesis of aliphatic amines from nitroalkenes and nitroalkanes (up to 90% yield). This photoenzymatic reduction overcomes the competing bio-Nef reaction, typically hindering the complete enzymatic reduction of nitroaliphatics. The results highlight the usefulness of nitroreductases to create selective photoenzymatic systems for the synthesis of precious chemicals, and the effectiveness of chlorophyll as an innocuous photocatalyst, enabling the use of sunlight to drive the photobiocatalytic reactions.

Chemoenzymatic Asymmetric Synthesis of Complex Heterocycles: Dihydrobenzoxazinones and Dihydroquinoxalinones.

Chiral dihydrobenzoxazinones and dihydroquinoxalinones serve as essential building blocks for pharmaceuticals and agrochemicals. Here, we report short chemoenzymatic synthesis routes for the facile preparation of these complex heterocycles in an optically pure form. These synthetic routes involve a highly stereoselective hydroamination step catalyzed by ethylenediamine-N,N'-disuccinic acid lyase (EDDS lyase). This enzyme is capable of catalyzing the asymmetric addition of various substituted 2-aminophenols to fumarate to give a broad range of substituted N-(2-hydroxyphenyl)-l-aspartic acids with excellent enantiomeric excess (ee up to >99%). This biocatalytic hydroamination step was combined with an acid-catalyzed esterification-cyclization sequence to convert the enzymatically generated noncanonical amino acids into the desired dihydrobenzoxazinones in good overall yield (up to 63%) and high optical purity (ee up to >99%). By means of a similar one-pot, two-step chemoenzymatic approach, enantioenriched dihydroquinoxalinones (ee up to >99%) were prepared in good overall yield (up to 78%) using water as solvent for both steps. These chemoenzymatic methodologies offer attractive alternative routes to challenging dihydrobenzoxazinones and dihydroquinoxalinones, starting from simple and commercially available achiral building blocks.

Prunella vulgaris L: Critical Pharmacological, Expository Traditional Uses and Extensive Phytochemistry: A Review.

BACKGROUND: Prunella vulgaris , family Lamiaceae also known as self-heal, has been traditionally used as an expectorant, anti-inflammatory, anti-pyretic, and anti-rheumatic. Due to the widespread distribution of the plant, Vulgaris is also called 'vulgar' in Latin adjective meaning common. OBJECTIVE: The objective of this review was to describe the relevant aspects of phytochemistry and therapeutic uses of different fractions as well as isolated compounds from Prunella vulgaris . An attempt was also made to enumerate the possible leads, e.g . betulinic acid, oleanolic acid, ursolic acid, umbelliferone, scopoletin, esculetin, luteolin, homoorientin, Rosmarinic acid and cinaroside, for further development. METHOD: For peer-reviewed research literature, we undertook a structured search of bibliographic databases using a focused review question. Scientific databases such as PubMed, Scopus, Science Direct, and Google Scholar were searched. RESULTS: Phytochemistry of Prunella vulgaris (PV) after a thorough literature survey revealed varied and copious metabolites, such as triterpenoids, phenolic acid, sterols, carbohydrates, coumarins, fatty acids, and volatile oils. Many of these compounds have been found to possess a wide range of biological activities per se, including anti-microbial, immunosuppressive, anti-cancer, cardio- protective, anti-allergic and anti-inflammatory activities. CONCLUSION: Prunella vulgaris is a medicinal plant of immense medicinal importance having a variety of compounds, such as triterpenoids, phenolic acid, sterols, carbohydrates, coumarins, fatty acids, and volatile oils, and diversity in the pharmacological spectrum. The plant could be further exploited to isolate the various biologically active constituents responsible for its activity.

Phenothiazine: A Better Scaffold against Tuberculosis.

The incidence of Tuberculosis (TB) is baffling in developing countries due to the increase in multidrug-resistant and extensively drug-resistant TB. Therefore, drugs acting through different mechanisms are in dire need to counter the resistant strains. Various chemical scaffolds are being investigated against tuberculosis, among them the molecules containing phenothiazine nucleus are found to be more effective against both susceptible and resistant strains of M. tuberculosis. In addition, the efficacy of first-line drugs has been found to be enhanced on supplementary treatment with phenothiazines. The present review provides an overview of the phenothiazine based molecules which were investigated during the last ten years for their anti-tubercular activity.