Bicyclic Ring Research Articles

Aza-Wacker Cyclization Toward the Bridged Core of FR901483

AbstractA nine-step synthetic route to access the tricyclic core of FR901483 is reported, featuring a key aza-Wacker cyclization step to construct an α-tertiary amine (ATA) in the bridged structure. The aza-Wacker protocol can tolerate both exocyclic and endocyclic double bonds, providing viable access to various bridged bicyclic rings bearing an ATA (e.g., 6-azabicyclo[3.2.1]octane, 7-azabicyclo[3.3.1]nonane, and 7-azabicyclo[4.2.1]nonane) in good to excellent yields. The synthetic studies presented herein enable structural derivatization of FR901483 to further exploit its compelling biological activities.

Oxidative bicyclic ring system formation involving indole diterpene biosynthesis: Remarkable substrate tolerance of a prenyltransferase and flavoprotein oxidase

Oxidative modifications are key biosynthetic processes responsible for expanding the structural diversity of indole diterpenes (IDTs). In this study, we focused on the function of prenyltransferases and flavoprotein oxidases for the synthesis of nodulisporic acid-type and shearinine-type bicyclic rings found on the indole moiety. An in vitro enzymatic reaction of a prenyltransferase JanD, which mediates diprenylation at the C5- and C6-positions, revealed that JanD recognizes a C13‑hydroxy group on the diterpene moiety. Subsequent enzymatic reactions with flavoprotein oxidases, JanO, and NodO, indicated that JanO can accommodate penta/hexacyclic IDTs, while NodO exhibits strict substrate specificity toward pentacyclic IDTs. The broad substrate tolerance of JanD and JanO provides opportunities for the synthesis of unnatural IDTs based on artificial reconstitution in a heterologous host.

Structural evolution and electronic properties of doped boron clusters Ta2Bn (n = 10 ∼ 20): Ta2B16 and Ta2B18 with strong aromaticity

In this work, we combine the CALYPSO method with DFT calculations to conduct a comprehensive structural search of Ta2Bn (n = 10 ∼ 20) clusters. Among all the candidate structures obtained by CALYPSO searching, the structures of ground state Ta2Bn clusters at each size are determined according to their total energy and symmetry. The relative stability analysis indicates that the ground state Ta2B16 and Ta2B18 clusters with the unique bicyclic boron ring and two Ta atoms as axes exhibit excellent stability in the studied range, with their HOMO-LUMO gaps of 2.374 and 2.640 eV, respectively. The bonding analyses reveal that the strong interaction between two Ta atoms and the outer B16/18 bicyclic ring dominates their significant stability, especially the interaction between Ta-d AOs and B-s/p AOs. It is confirmed that both Ta2B16 and Ta2B18 have strong aromaticity by examining the isochemical shielding surface (ICSS). Finally, the strong coupling between their outer boron rings (B16/18) and two Ta atoms inside the structures of Ta2B16 and Ta2B18 is further elucidated by the electronic absorption spectrum (UV–vis and CTS).

Synthesizing Polyurethane Using Isosorbide in Primary Alcohol Form, and Its Biocompatibility Properties.

Isosorbide is a bio-based renewable resource that has been utilized as a stiffness component in the synthesis of novel polymers. Modified isosorbide-based bis(2-hydroxyethyl)isosorbide (BHIS) has favorable structural features, such as fused bicyclic rings and a primary hydroxyl function with improved reactivity to polymerization when compared to isosorbide itself. Polyurethane series (PBH PU series) using polycarbonate diol (PCD) and bis(2-hydroxyethyl)isosorbide (BHIS) were polymerized through a simple, one-shot polymerization without a catalyst using various ratios of BHIS, PCD, and hexamethylene diisocyanate (HDI). The synthesized BHIS and PUs were characterized using proton nuclear magnetic resonance (1H-NMR), Fourier transform infrared (FT-IR), differential scanning calorimetry (DSC), and mechanical testing. To determine the feasibility of using these PUs as biomedical materials, we investigated the effects of their BHIS content on PBH PU series physical and mechanical properties. The PBH PU series has excellent elasticity, with a breaking strain ranging from 686.55 to 984.69% at a 33.26 to 63.87 MPa tensile stress. The material showed superb biocompatibility with its high adhesion and proliferation in the bone marrow cells. Given their outstanding mechanical properties and biocompatibility, the polymerized bio-based PUs can contribute toward various applications in the medical field.

Discovery of Subnanomolar Inhibitors of 4-Hydroxyphenylpyruvate Dioxygenase via Structure-Based Rational Design

High-potency 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors are usually featured by time-dependent inhibition. However, the molecular mechanism underlying time-dependent inhibition by HPPD inhibitors has not been fully elucidated. Here, based on the determination of the HPPD binding mode of natural products, the π-π sandwich stacking interaction was found to be a critical element determining time-dependent inhibition. This result implied that, for the time-dependent inhibitors, strengthening the π-π sandwich stacking interaction might improve their inhibitory efficacy. Consequently, modification with one methyl group on the bicyclic ring of quinazolindione inhibitors was achieved, thereby strengthening the stacking interaction and significantly improving the inhibitory efficacy. Further introduction of bulkier hydrophobic substituents with higher flexibility resulted in a series of HPPD inhibitors with outstanding subnanomolar potency. Exploration of the time-dependent inhibition mechanism and molecular design based on the exploration results are very successful cases of structure-based rational design and provide a guiding reference for future development of HPPD inhibitors.

Brief insight into the in silico properties, structure–activity relationships and biotransformation of fruquintinib, an anticancer drug of a new generation containing a privileged benzofuran scaffold

Current trends in drug design notably consider so-called privileged scaffolds as the core structural fragments with decisive impact on affinity to properly chosen biological targets, potency, selectivity and toxicological characteristics of drugs and prospective drug candidates. Fruquintinib (1) is a novel synthetic selective inhibitor of vascular endothelial growth factor receptor (VEGFR) isoforms, i.e., VEGFR-1, VEGFR-2 and VEGFR-3. The therapeutic agent (1) consists of a flat bicyclic heteroaromatic ring, in which two nitrogens are suitablyincorporated, a core bicyclic heteroaromatic ring – privileged (substituted) benzofuran scaffold, and a pair of hydrogen bond (H-bond) donor and acceptor group, i.e., amide functional moiety. Fruquintinib (1) was first approved in China for the treatment of metastatic colorectal cancer, a severe malignant disease with a high mortality rate. The review article offered a brief insight into the topic of privileged structures, their drug- -like ranges of several parameters, pharmacodynamic characteristics of fruquintinib (1) and various in silico descriptors characterizing drug’s structural and physicochemical properties (molecular weight, number of heavy atoms, number of aromatic heavy atoms, fraction of sp3 C-atoms, number of H-bond acceptors, number of H-bond donors, total polar surface area, molar refractivity, molecular volume as well as parameters of lipophilicity and solubility). Some of these descriptors were related to pharmacokinetics and distribution of fruquintinib (1), and, in addition, might help predict its ability to cross passively the blood–brain barrier (BBB). Moreover, a possible connection between the induction potential on cytochrome P450 isoenzymes (CYP1A2 and CYP3A4) and passive transport of a given drug into the central nervous system via BBB was investigated. Current clinical experience and future directions regarding of fruquintinib (1) were also briefly outlined.

Discovery of N-sulfonylated aminosalicylic acids as dual MCL-1/BCL-xL inhibitors.

The anti-apoptotic protein MCL-1, which is overexpressed in multiple cancers, is presently a focus for the development of targeted drugs in oncology. We previously discovered inhibitors of MCL-1 based on 1-sulfonylated 1,2,3,4-tetrahydroquinoline-6-carboxylic acids ("1,6-THQs"). However, with the nitrogen atom constrained in the bicyclic ring, we were unable to modify the alkyl portion of the tertiary sulfonamide functionality. Moreover, the introduction of additional functional groups onto the benzene ring portion of the THQ bicycle would not be trivial. Therefore, we elected to deconstruct the piperidine-type ring of the 6-carboxy-THQ lead to create a new 4-aminobenzoic acid scaffold. Given its simplicity, this permitted us to introduce diversity at the sulfonamide nitrogen, as well as vary the positions and substituents of the benzene ring. One of our most potent MCL-1 inhibitors, 6e-OH, exhibited a K i of 0.778 μM. Heteronuclear single quantum coherence experiments suggested 6e-OH bound in the canonical BH3-binding groove, with significant perturbations of R263, which forms a salt bridge with MCL-1's pro-apoptotic binding partners, as well as residues in the p2 pocket. Selectivity studies indicated that our compounds are dual inhibitors of MCL-1 and BCL-xL, with 17cd the most potent dual inhibitor: K i = 0.629 μM (MCL-1), 1.67 μM (BCL-xL). Whilst selective inhibitors may be more desirable in certain instances, polypharmacological agents whose additional target(s) address other pathways associated with the disease state, or serve to counter resistance mechanisms to the primary target, may prove particularly effective therapeutics. Since selective MCL-1 inhibition may be thwarted by overexpression of sister anti-apoptotic proteins, including BCL-xL and BCL-2, we believe our work lays a solid foundation towards the development of multi-targeting anti-cancer drugs.

Tetramate derivatives by chemoselective Dieckmann ring closure of allo-phenylserines, and their antibacterial activity.

A general route which provides direct access to substituted bicyclic tetramates, making use of Dieckmann cyclisation of oxazolidine derivatives derived from allo-phenylserines, is reported. Of interest is the high level of diastereoselectivity observed for the N-acylation reaction of oxazolidines and the complete chemoselectivity of their ring closure in the Dieckmann cyclisation. Significantly, the sense of the chemoselectivity is different to earlier reported threo-phenylserine systems, showing the importance of steric bulk around the bicyclic ring system. The derived C7-carboxamidotetramates, but not C7-acyl systems, exhibited potent antibacterial activity against MRSA, with the most active compounds exhibiting well-defined physicochemical and structure-activity properties. This work clearly demonstrates that densely functionalised tetramates are both readily available and may exhibit high levels of antibacterial activity.

Cofactor-Free Dioxygenases-Catalyzed Reaction Pathway via Proton-Coupled Electron Transfer.

Understanding the general mechanism of the metal-free and cofactor-free oxidases and oxygenases catalyzed activation of triplet O2 is one of the most challenging questions in the field of enzymatic catalysis. Herein, we have performed Quantum Mechanics/Molecular Mechanics (QM/MM) multiscale simulations to reveal the detailed mechanism of the HOD catalyzed (i.e., 1-H-3-hydroxy-4-oxoquinaldine 2,4-dioxygenase from Arthrobacter nitroguajacolicus Rü61a) decomposition of N-heteroaromatic compounds. The complete catalytic mechanism includes four steps: (1) proton transfer from 1-H-3-hydroxy-4-oxoquinaldine (QND) substrate to His251 residue coupled with an electron transfer from QND to triplet O2 (i.e., PCET), (2) formation of C-O bond via an open-shell singlet diradical recombination pathway, (3) ring-closure to form a bicyclic ring, and (4) dissociation of CO. The dissociation of CO is determined as the rate-limiting step, and its calculated energy barrier of 14.9 kcal/mol is consistent with the 15.5 kcal/mol barrier derived from experimental kinetic data. The mechanistic profile is not only valuable for understanding the fundamental pathway of cofactor-free oxidases and oxygenases-catalyzed reactions involving the triplet O2 activation but also discloses a new pathway that undergoes the processes of PCET and open-shell singlet transition state.

1650. Efficacy of β-Lactam Therapy against Infections Caused by Metallo-β-lactamase (MBL)-Producing Enterobacterales: Bridging the Susceptibility Testing Gap

Abstract Background In vitro-in vivo discordance in the activity of β-lactams against MBL-producing Enterobacterales has been described. This discordance is likely attributed to the supra-physiologic zinc level in the in vitro testing media, which facilitates the bicyclic β-lactam ring hydrolysis. In this study, we compared the outcome of empirical non-MBL-active β-lactam therapy (carbapenems and ceftazidime/avibactam) and MBL-active β-lactam therapy (ceftazidime/avibactam plus aztreonam) among patients with bloodstream infections due to NDM-producing Klebsiella pneumoniae. Validation of the efficacy of carbapenem in a murine septicemia model was conducted. In vitro susceptibility testing conditions were altered to better predict the in vivo outcome. Methods A retrospective observational study of patients admitted to hospitals in Italy. The primary outcome was 14-day all-cause mortality. Cox regression analysis was performed to evaluate primary outcome. Kaplan Meier survival and log-rank test were used to compare 14-day mortality between patient’s cohorts. Septicemia was induced in mice via intraperitoneal inoculation with the isolates retrieved from the patients then clinical exposure of meropenem (MEM; 2 g q8h 3h infusion) was given for 2 days. Survival was recorded for 4 days and compared with sham controls. Unbound zinc levels were measured in human and infected mice plasma. MEM MICs were determined in Mueller Hinton Broth (MHB) and MHB adjusted to the physiologic zinc levels. Results Of the patients identified, 29 received empirical non-MBL-active β-lactams for median duration 4 days while 29 received MBL-active β-lactams. The 14-day mortality rate was 21% in the non-MBL-active group vs 14% in the MBL-active group (P = 0.73) and survival patterns were not significantly different (Fig. 1). Cox regression showed that use of non-MBL-active therapy was not associated with significantly increased 14-day mortality (hazard ratio = 1.45; P = 0.57). MEM treatment resulted in protection from mortality in mice (Fig. 2). MEM MICs in zinc-adjusted MHB were 1- to > 16-fold lowered relative to MICs in MHB ( ≥ 64 mg/L). Conclusion Our data provide foundational support to help establish PK/PD relationships using MICs derived in physiologic zinc levels which may better predict β-lactam therapy outcome. Disclosures Kamilia Abdelraouf, PhD, Evopoint Biosciences Co., Ltd: Grant/Research Support|Venatorx Pharmaceuticals, Inc.: Grant/Research Support Christian M. Gill, PharmD, Everest Medicines, Shionogi, Cepheid: Grant/Research Support Matthew Gethers, PhD, Thermo Fisher: Employee Marco Falcone, MD, PhD, GILEAD: Grant/Research Support|GSK: Honoraria|MENARINI: Advisor/Consultant|MENARINI: Grant/Research Support|MSD: Honoraria|PFIZER: Honoraria|SHIONOGI: Grant/Research Support Francesco Menichetti, n/a, Aneglini: Advisor/Consultant|Aneglini: Board Member|Aneglini: Grant/Research Support|Aneglini: Honoraria|Astellas: Advisor/Consultant|Astellas: Honoraria|Becton: Advisor/Consultant|Becton: Honoraria|bioMérieux: Advisor/Consultant|bioMérieux: Honoraria|Biotest: Advisor/Consultant|Biotest: Board Member|Biotest: Honoraria|Bristol-Myers Squibb: Advisor/Consultant|Bristol-Myers Squibb: Honoraria|Correvio: Advisor/Consultant|Correvio: Speaker honoraria|Dickinson: Advisor/Consultant|Dickinson: Honoraria|Gilead: Advisor/Consultant|Gilead: Grant/Research Support|Janssen: Advisor/Consultant|Janssen: Honoraria|MSD: Advisor/Consultant|MSD: Speaker honoraria|Nordic pharma: Board Member|Nordic pharma: Honoraria|Pfizer: Advisor/Consultant|Pfizer: Honoraria|Shionogi: Advisor/Consultant|Shionogi: Honoraria|ViiV: Advisor/Consultant|ViiV: Honoraria David P. Nicolau, PharmD, Shionogi: Grant/Research Support.

Bifunctional Pt/Hβ catalyzed alkylation and hydrodeoxygenation of phenol and cyclohexanol in one-pot to synthesize high-density fuels

Synthesis of fuels from lignin bio-oil feedstock significantly alleviates energy crises and environmental pollution. Phenol is the simplest model compound for lignin bio-oil feedstocks, and the synthesis of fuel precursors from phenol through alkylation has received increasing attention. Here we report a one-pot strategy for preparing polycyclic alkane high-density fuels from phenol and cyclohexanol over bifunctional Pt/Hβ catalyst by combining alkylation with following hydrodeoxygenation (HDO). The activity of different zeolites for catalyzing the alkylation of phenol and cyclohexanol was explored. It was found that the larger pore size of alkali treated Hβ would not limit the production of polycyclic compounds, and good acid content in a particular mesoporous specific surface area can speed up the reaction rate. The one-pot reaction conditions were then optimized. When the alkali treatment concentration is 0.2 mol/L, the metal loading is 0.2 wt%, and the molar ratio of phenol and cyclohexanol is 1:1, the highest conversion of phenol can reach more than 83 %. The selectivity of alkylphenol can reach more than 97 %, and the yield of bicyclic and tricyclic rings in the final product after HDO can reach 83.42 %. The bifunctional catalyst can also realize the coupling of other acid-catalyzed carbon growth reactions and metal-catalyzed HDO reactions, which allows the direct synthesis of fuel from lignin oil or other biomass compounds.

Structure Revision of the Sesquiterpene Nordine Based on NMR Spectroscopic Analysis and X-ray Crystallography.

Nordine was reported to be an unusual humulene-type macrocyclic sesquiterpenoid that contains an ether-bridged bicyclic ring between C-10 and C-6 with a hydroxy group at position 2. Here, we report the structure revision of nordine based on incongruities found for carbon chemical shifts in the originally proposed structure, in addition to formation of a diacetylated derivative. As expected, a single-crystal X-ray diffraction analysis unambiguously confirmed our proposal that the nordine (1) structure contains an ether-bridged bicyclic ring between C-10 and C-7 and hydroxy groups at C-2 and C-6. Furthermore, the absolute configuration was determined by ECD spectroscopic analysis.

Cascade Cyclopolymerization of 5-Ethynyl-1,8-Nonadiyne Derivatives to Synthesize Low Band Gap Conjugated Polyacetylenes Containing a Fused Bicyclic Structure.

Cyclopolymerization is a powerful method for synthesizing polyacetylenes containing four- to seven-membered rings. However, the structure of the repeat unit only consists of mono-cycloalkene due to the single cyclization of diyne monomers. Herein, we demonstrate a novel cascade cyclopolymerization to synthesize polyacetylenes containing fused bicyclic rings from triyne monomers containing bulky dendrons via sequential cascade ring-closing metathesis. These dendrons provided solubility and stability to the rigid bicyclic polyacetylene backbone. In addition, we controlled the regioselectivity of the catalyst approach by altering its structure and synthesized polymers containing fused bicyclo[4,3,0] or [4,4,0] rings with high molecular weights of up to 120 kg mol-1 . Interestingly, the resulting polymers showed narrower band gaps (down to 1.6 eV) than polymers with mono-cycloalkene repeat units due to the planarization of the conjugated segment resulting from the fused bicyclic structure.

Cascade Cyclopolymerization of 5‐Ethynyl‐1,8‐Nonadiyne Derivatives to Synthesize Low Band Gap Conjugated Polyacetylenes Containing a Fused Bicyclic Structure

AbstractCyclopolymerization is a powerful method for synthesizing polyacetylenes containing four‐ to seven‐membered rings. However, the structure of the repeat unit only consists of mono‐cycloalkene due to the single cyclization of diyne monomers. Herein, we demonstrate a novel cascade cyclopolymerization to synthesize polyacetylenes containing fused bicyclic rings from triyne monomers containing bulky dendrons via sequential cascade ring‐closing metathesis. These dendrons provided solubility and stability to the rigid bicyclic polyacetylene backbone. In addition, we controlled the regioselectivity of the catalyst approach by altering its structure and synthesized polymers containing fused bicyclo[4,3,0] or [4,4,0] rings with high molecular weights of up to 120 kg mol−1. Interestingly, the resulting polymers showed narrower band gaps (down to 1.6 eV) than polymers with mono‐cycloalkene repeat units due to the planarization of the conjugated segment resulting from the fused bicyclic structure.

Isoquinolone derivatives as lysophosphatidic acid receptor 5 (LPA5) antagonists: Investigation of structure-activity relationships, ADME properties and analgesic effects

Blockade of lysophosphatidic acid receptor 5 (LPA5) by a recently reported antagonist AS2717638 (2) attenuated inflammatory and neuropathic pains, although it showed moderate in vivo efficacy and its structure-activity relationships and the ADME properties are little studied. We therefore designed and synthesized a series of isoquinolone derivatives and evaluated their potency in LPA5 calcium mobilization and cAMP assays. Our results show that substituted phenyl groups or bicyclic aromatic rings such as benzothiophenes or benzofurans are tolerated at the 2-position, 4-substituted piperidines are favored at the 4-position, and methoxy groups at the 6- and 7-positions are essential for activity. Compounds 65 and 66 showed comparable in vitro potency, excellent selectivity against LPA1-LPA4 and >50 other GPCRs, moderate metabolic stability, and high aqueous solubility and brain permeability. Both 65 and 66 significantly attenuated nociceptive hypersensitivity at lower doses than 2 and had longer-lasting effects in an inflammatory pain model, and 66 also dose-dependently reduced mechanical allodynia in the chronic constriction injury model and opioid-induced hyperalgesia at doses that had no effect on the locomotion in rats. These results suggest that these isoquinolone derivatives as LPA5 antagonists are of promise as potential analgesics.

Acetamidobenzoxazolone scaffold as a promising translocator protein (18 kDa, TSPO) marker for neuroinflammation imaging: Advancement in last decennial period.

Inflammation has been linked to the onset and progression of a wide range of neuropathological disorders. The well-conserved outer mitochondrial membrane 18 kDa translocator protein (TSPO) is perceived as an in vivo neuroinflammation marker. A dearth of a reference region, genetic disparity influencing the ligand's affinity for TSPO, and a substantial signal in the endothelium of the brain veins contributes toward complications in quantifying TSPO positron emission tomography (PET) image. Up to the present time several radiotracers based on different pharmacophore such as (R)[11 C]PK11195, [18 F]DPA714, [11 C]PBR28, [11 C]ER176, and many more have been recognized for envisaging the prominent TSPO level observed in neurological conditions. Recently acetamidobenzoxazolone (ABO) scaffold, a bicyclic ring system composed of a phenyl ring fused to a carbamate and its substituted radiolabelled analogues especially at C-5 position has evidenced encouraging outcomes as next generation of TSPO PET ligands. Diverse ABO framework-based TSPO ligands have been designed embracing imperative aspects such as lipophilicity, metabolic profile, and capability to penetrate the blood-brain barrier apart from least effect of polymorphism (rs6971). Over the years numerous systematic literature reviews compiling different structural class of TSPO ligands characterized on the grounds of their binding affinity and metabolite profile have been reported but none is especially focused toward a fascinating benzoxazolone scaffold. This review exclusively bestows an overview of the recent advancements on ABO derivatives with neuroinflammation imaging potential and emphases on the structural features accountable for visualizing TSPO in-vivo with collation of published reports during last 10 years.

Crystal structure determination, Hirshfeld surface, crystal void, inter-molecular inter-action energy analyses, as well as DFT and energy framework calculations of 2-(4-oxo-4,5-di-hydro-1H-pyra-zolo[3,4-d]pyrimidin-1-yl)acetic acid.

In the title mol-ecule, C7H6N4O3, the bicyclic ring system is planar with the carb-oxy-methyl group inclined by 81.05 (5)° to this plane. In the crystal, corrugated layers parallel to (010) are generated by N-H⋯O, O-H⋯N and C-H⋯O hydrogen-bonding inter-actions. The layers are associated through C-H⋯π(ring) inter-actions. A Hirshfeld surface analysis indicates that the most important contributions to the crystal packing are from H⋯O/O⋯H (34.8%), H⋯N/N⋯H (19.3%) and H⋯H (18.1%) inter-actions. The volume of the crystal voids and the percentage of free space were calculated to be 176.30 Å3 and 10.94%, showing that there is no large cavity in the crystal packing. Computational methods revealed O-H⋯N, N-H⋯O and C-H⋯O hydrogen-bonding energies of 76.3, 55.2, 32.8 and 19.1 kJ mol-1, respectively. Evaluations of the electrostatic, dispersion and total energy frameworks indicate that the stabilization is dominated via dispersion energy contributions. Moreover, the optimized mol-ecular structure, using density functional theory (DFT) at the B3LYP/6-311G(d,p) level, was compared with the experimentally determined one. The HOMO-LUMO energy gap was determined and the mol-ecular electrostatic potential (MEP) surface was calculated at the B3LYP/6-31G level to predict sites for electrophilic and nucleophilic attacks.

Norditerpenoids biosynthesized by variediene synthase-associated P450 machinery along with modifications by the host cell Aspergillus oryzae

The chemical diversity of terpenoids is typically established by terpene synthase-catalyzed cyclization and diversified by post-tailoring modifications. Fungal bifunctional terpene synthase (BFTS) associated P450 enzymes have shown significant catalytic potentials through the development of various new terpenoids with different biological activities. This study discovered the BFTS and its related gene cluster from the plant endophytic fungus Didymosphaeria variabile 17020. Heterologous expression of the BFTS in Saccharomyces cerevisiae resulted in the characterization of a major product diterpene variediene (1), along with two new minor products neovariediene and neoflexibilene. Further heterologous expression of the BFTS and one cytochrome P450 enzyme VndE (CYP6138B1) in Aspergillus oryzae NSAR1 led to the identification of seven norditerpenoids (19 carbons) with a structurally unique 5/5 bicyclic ring system. Interestingly, in vivo experiments suggested that the cyclized terpene variediene (1) was modified by VndE along with the endogenous enzymes from the host cell A. oryzae through serial chemical conversions, followed by multi-site hydroxylation via A. oryzae endogenous enzymes. Our work revealed that the two-enzymes biosynthetic system and host cell machinery could produce structurally unique terpenoids.

Benzimidazole derivatives: A versatile scaffold for drug development against Helicobacter pylori-related diseases.

Helicobacter pylori (H.pylori) is a microaerophilic gastric pathogen and a major contributor to chronic atrophic gastritis, peptic ulcer, and gastric malignancies. The increasing prevalence of H.pylori infection and its related diseases, such as gastric cancer (GC), motivates medicinal chemists to seek for more effective multi-targeting drugs to prevent and treat H.pylori-related clinical complications. Benzimidazole, a hetero-aromatic bicyclic ring compound, has claimed a prominent role in medicinal chemistry owing to its broad range of biological activities, including antibacterial, antiviral, antidiabetic, and anticancer activities. Studies highlight the promising therapeutic potential of benzimidazole derivatives in the treatment of H.pylori-related clinical complications such as gastric infection, gastritis, peptic ulcer, and GC. Accordingly, we here aimed to scrutinize the role of active molecules of benzimidazole derivatives as potential antibacterial, anti-urease, anti-inflammatory, anti-ulcerative, and anticancer agents, which are expected to find their ways to the clinical setting sooner or later. Due to the role of structural moieties in determining the biological behaviors of benzimidazole derivatives, we explored the structure-activity relationship (SAR) of these compounds to further expand the scope of design of and research on new drugs against H.pylori-related diseases.

Indazole and its Derivatives in Cardiovascular Diseases: Overview, Current Scenario, and Future Perspectives.

Indazoles are a class of heterocyclic compounds with a bicyclic ring structure composed of a pyrazole ring and a benzene ring. Indazole-containing compounds with various functional groups have important pharmacological activities and can be used as structural motifs in designing novel drug molecules. Some of the indazole-containing molecules are approved by FDA and are already in the market. However, very few drugs with indazole rings have been developed against cardiovascular diseases. This review aims to summarize the structural and pharmacological functions of indazole derivatives which have shown efficacy against cardiovascular pathologies in experimental settings.