Bicyclic Research Articles

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.

Theoretical Investigation on C11H8 Bicyclic Carbene and Allene Isomers

Recent studies postulate that the presence of polycyclic aromatic hydrocarbons (PAHs) in the interstellar medium (ISM) could have been formed through resonance-stabilized arylcarbene intermediates. However, identifying most of these reactive intermediates is very challenging experimentally due to their metastability and other experimental constrains. Thus, computational studies that cover the thermodynamic versus kinetic stability of various possible structures would be beneficial for successfully identifying new molecules either in the laboratory and/or in the ISM. In this paper, more than four hundred C11H8 carbene isomers have been theoretically investigated employing density functional theory (DFT). Hybrid density functionals B3LYP and ωB97XD with 6-311 + G (d,p) basis set have been used for singlet electronic states, whereas, triplet spin states were optimized at the same level using an unrestricted Hartree-Fock wavefunction. Although the skeletal structures of C11H8 can be categorized into monocyclic, bicyclic, tricyclic, tetracyclic and acyclic isomers, bicyclic carbenes have shown better stability due to the presence of resonance stabilized azulenyl/naphthyl rings. In this category, some isomers (1-, 2-, 5- and 6-azulenylcarbenes and 1- and 2-naphthylcarbenes) have also been detected recently in the laboratory and simple aromatic carbenes such as cyclopropenylidene and its homologues are detected in the ISM. Thus, we have systematically investigated the energetic and spectroscopic properties of resonance stabilized 5-, 6-, 7- and 8-membered ring containing bicyclic isomers of C11H8 and the fingerprint regions of the infrared spectrum for each class of these bicyclic compounds.

Modulating the selectivity of inhibitors for prolyl oligopeptidase inhibitors and fibroblast activation protein-α for different indications

We have previously described several different chemical series of bicyclic prolyl oligopeptidase (POP) inhibitors as probes for neurodegenerative diseases that demonstrated nanomolar activity in vitro and submicromolar activity in cellulo. The more recent implication of POP in cancer, together with homologous fibroblast activation protein α (FAP), implicated in tumor growth, led us to consider developing POP/FAP dual inhibitors as a promising strategy for the development of cancer therapeutics. At this stage, we thought to evaluate the requirements for selectivity of inhibitors for POP over FAP and to evaluate molecular platforms that would enable the development of selective POP and dual POP/FAP inhibitors. We report herein docking-guided design of a new bicyclic scaffold and synthesis of both covalent and non-covalent bicyclic inhibitors. Biological evaluation of first-of-their-kind [4.3.0] bicyclic compounds confirmed that reactive groups, or covalent warheads, are required for inhibitor activity. This work ultimately led to one scaffold yielding new POP-selective inhibitors and a dual inhibitor equipotent to the only drug targeting FAP and POP that ever reached clinical trials.

Importance of Indazole against Neurological Disorders.

Indazole is a nitrogen-containing bicyclic compound, having three tautomeric forms: 1Hindazole, 2H-indazole, and 3H-indazole. Mostly, they are considered as 1H-indazole tautomeric forms, although they have the potential to tautomerism to 2H- and 3H-indazole forms. Indazoles are involved in a wide variety of biological and enzymatic processes. Therefore, they exhibit a series of pharmacological activities. Indazoles show potent activities against neurological disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), mood disorders, etc., by inhibiting different signaling pathways and the generation of neurotransmitters and activation of enzyme activity. They effectively prevent neurological diseases by different mechanisms, such as by inhibiting the monoamine oxidase (MAO) and kinase enzymes like Glycogen synthase kinase 3 (GSK3), and leucinerich repeat kinase enzyme 2 (LRRK2). In this article, we have discussed multiple causative strategies of indazole to treat neurological diseases. This has aroused special attention in the discovery of the novel indazoles and their biological activities.

Impact of Indazole Scaffold as Antibacterial and Antifungal Agent.

Heterocycles consisting of a nitrogen atom, Indazole, is a pungent, biological, heterocyclic, bicyclic compound possessing electron-rich portions. Indazole is composed of two nitrogen atoms put under the azoles family, further called isoindazolone. It is colorless solid nitrogen- containing heterocyclics with atomic formula-C7H6N2 are extraordinary scaffolds, still identified as isoindazole. Therefore, analogs of Indazole have experienced expert approaches in later times because of its special biological properties, such as anti-microbial, anti-inflammatory, anticancer, anti- HIV and antihypertensive actions. 1H-indazole and 2H-indazole are two toutomeric forms of Indazole. Sometimes, indazole produces three tautomeric forms that are 1H, 2H and 3H tautomers of indazole. 1H-indazole is reliable than 2H-indazole. We should note that a series of derivatives of indazole having 2H toutomers follow hybridization of cyclic systems and act as anti-inflammatory as well as anti-microbial compounds. It formed Indazole itself and derivatives of Indazole in natural products. A sequence of N-methyl-3-aryl inazoles has dominant against bacterial strains like xanthomon as campstris, Baillus cereus, Escherichia coli, Bacillus megaterium and a fungal strain candida albicans found by in-vitro anti-microbial study of indazole derivatives.

Biological Screening and Structure Activity relationship of Benzothiazole

Benzothiazole is a heterocyclic compound having nitrogen and sulphur. It's a bicyclic compound with a thiazole with benzene ring fused together. As per a review of the literature, benzothiazole is a primary moiety for the development of anticancer, antidiabetic, antioxidant, analgesic, and anti-inflammatory, antibacterial, antifungal, antiviral, anticonvulsant, antidepressant, antioxidant, and hepatoprotective agents. As a result, a list of biologically active benzothiazole derivatives has indeed been compiled in this study. The structure-activity relationship is analyzed based on the biological activities of benzothiazole derivatives and their substitution pattern. We also examined the mechanism of action of various benzothiazole derivatives, which can benefit researchers in the creation of new benzothiazole derivatives.

Inhibition of Plasmodium falciparum phenylalanine tRNA synthetase provides opportunity for antimalarial drug development

Bicyclic azetidine compounds possess antimalarial activity via targeting of the cytoplasmic Plasmodium falciparum (Pf) protein translation enzyme phenylalanine-tRNA synthetase (cFRS). These drugs kill parasites both invitro and invivo, including the blood, liver, and transmission developmental stages. Here we present the co-crystal structure of PfcFRS with a potent inhibitor, the bicyclic azetidine BRD7929. Our studies reveal high-affinity binding of BRD7929 with PfcFRS along with exquisite specificity compared with the human enzyme, leading in turn to potent and selective inhibition of the parasite enzyme. Our co-crystal structure shows that BRD7929 binds in the active site in the α subunit of PfcFRS, where it occupies the amino acid site, an auxiliary site, and partially the ATP site. This structural snapshot of inhibitor-bound PfcFRS thus provides a platform for the structure-guided optimization of novel antimalarial compounds.

Reactions of a Four-Membered Borete with Carbon, Silicon, and Gallium Donor Ligands: Fused and Spiro-Type Boracycles.

Donor‐acceptor cyclopropanes or cyclobutanes are dipolar reagents, which are widely used in the synthesis of complex organic (hetero)cycles in ring expansion reactions. Applying this concept to boron containing heterocycles, the four‐membered borete cyclo‐iPr2N‐BC10H6 reacted with the carbon donor ligands 2,6‐xylylisonitrile and the carbene IMes :C(NMesCH)2 with ring expansion and ring fusion, respectively. In particular, the tetracyclic structure formed with IMes displays zwitterionic character and absorption in the visible region. In contrast to the carbene IMes, the heavier carbenoids :Si(NDippCH)2 and :Ga(AmIm) with a two‐coordinate donor atom afford spiro‐type bicyclic compounds, which display four‐coordinate geometry at silicon or gallium. (TD‐)DFT calculations provide deeper insight into the mechanism of formation and the absorption properties of these new compounds.

Evaluating Nicotine as a Cognitive Enhancer

Nicotine is a bicyclic chemical compound that is derived from tobacco plants. Due to its effect on the brain, nicotine is addictive and has long been used as a popular recreational drug. In numerous studies, nicotine has been shown to improve memory and reaction time performances. Some nicotine skin patch studies have exhibited characteristics of a possible treatment for cognitive impairments (Rezvani and Levin, 2001). Although many studies have shown that nicotine has cognitive-enhancing effects, there is not sufficient research conducted to examine the specific impacts of nicotine on reaction time. The aim of this study is to assess how reaction time differs before and after nicotine use for people who regularly use the drug and to test how the reaction times of non-users compares to those of regular users. This study was conducted on individuals aged 18 to 22. A Brain Gauge device and its associated software was used to collect reaction time data. Each user completed the Hardware Reaction Time test, which required the participant to press a button with their right index finger as soon as they felt the stimulus that was delivered to their right ring finger. It was found that people who did not use nicotine had faster reaction times than those who use nicotine regularly. However, regular nicotine users had slower reaction times before nicotine use as compared to after nicotine use. Although these results improve our understanding of the effects of nicotine use, there were limitations to the study. The experiment was not well-controlled as the environment of each participant was different, and the population tested consisted of mostly people in their early 20s. Further studies should be conducted with more controlled testing conditions and with a more diverse population.

Photoinitiator-free radical photopolymerization using polybrominated and polychlorinated aromatic methacrylates: Investigations on the mechanisms of initiation

In this study, pentabrominated and pentachlorinated phenyl methacrylate (PBPMA, PCPMA) were studied with respect to their suitability to initiate a photoinduced radical polymerization of an acrylic formulation without conventional photoinitiator. Real-time FTIR spectroscopy (RTIR) was used to study the kinetics of the polymerization reaction. Both halogenated monomers were found to be effective as initiators. Moreover, different experimental techniques such as laser flash photolysis (LFP), product analysis by GC/MS and FTIR spectroscopy as well as quantum chemical modeling were used to elucidate possible reaction pathways for the initiation of a photopolymerization reaction. A release of bromine radicals was observed by LFP after irradiation of PBPMA, which may initiate the polymerization similarly to the tetrabromophenyl methacrylate radicals. In contrast, no formation of free chlorine radicals from PCPMA was detected. Rather, GC/MS measurements after stationary photolysis indicated the formation of bicyclic isomers from PCPMA upon irradiation. Extensive quantum chemical modeling substantiated the formation of two different isomers. Accordingly, we propose that relocalization of the chlorine atom from the ortho position and subsequent ring closure via the methacrylate group may occur upon irradiation, which finally results in the formation of two bicyclic isomers with either a five- or a six-membered lactone ring. Spectra simulation and additional experiments by FTIR spectroscopy seem to indicate that the initiation of the photopolymerization with PCPMA might preferably proceed via the bicyclic molecule with the six-membered lactone ring and subsequent radical formation.

Pseudopterosins and Seco-Pseudopterosins: Compilation and Revision of Conflicting NMR Data, Names, Numbering Systems and Structural Elucidation

The present review is focussed on the structural elucidation of the bicyclic and tricyclic diterpenoid title compounds isolated from Pseudopterogorgia species, displaying a direct structural relationship with the biosynthetic precursor GGPP (regular isoprenoid skeletons). A compilation of 1H and 13C NMR spectroscopic data is presented grouped by similar spin systems. Apparent inconsistencies or potential missassignments are discussed, pointing out convenient revisions of data assignment to improve structure correlations. Some hemisynthetic intermediates in the structural elucidation process are included, as well as data of representative synthetic compounds.

Azaboratrane as an exceptionally potential organocatalyst for the activation of CO2 and coupling with epoxide

• The energy barrier for the CO 2 activation in the presence of AZAB is 9.35 kcal/mol. Also, the activation step is the rate-determining step of the coupling reaction of CO 2 with ethylene oxide. • The rate constant for the activation step and TOF for the coupling reaction of CO 2 with ethylene oxide is 0.0898 L/mol/s, and 1.74 × 10 9 , respectively. • The activation energy decreases to a great extent in the presence of polar solvents. Consequently, the rate constant value for the activation step increases to 3.8 × 10 3 L/mol/s in acetonitrile. • The coupling of CO 2 with epichlorohydrin is kinetically and thermodynamically more feasible than other epoxides. Excessive use of fossil fuels resulted in a massive increase in CO 2 concentration in the atmosphere, which led to serious environmental issues. Thus, necessary steps need to be employed to alleviate the excessive amount of CO 2 from the atmosphere, and converting CO 2 into industrially valuable chemicals (e.g., cyclic carbonates) could be the best possible strategy. But the stability of the CO 2 molecule poses an extreme challenge in this approach. Owing to the thermodynamic stability of the CO 2 molecule, an exclusive bicyclic compound, azaboratrane (AZAB), has been theoretically investigated in the present work. The density functional theory (DFT) based studies were conducted to probe the catalytic action of the AZAB. The plausible mechanisms for the coupling reaction of CO 2 with epoxides were proposed and investigated. The effects of the solvents on the CO 2 coupling with epoxides in the presence of AZAB were also studied. Finally, a comparative analysis of different azatranes has been conducted to showcase the novelty of the presented catalyst. The result shows that the coupling reaction proceeds via CO 2 activation mechanism. The energy barrier for the activation was 9.35 kcal/mol, which further decreases to a great extent in the presence of highly polar solvents. Also, the calculated rate constant for the activation step was 0.08 L/mol/s. The rate constant tends to increase by increasing the temperature and polarity of the solvent. Thus, AZAB is found to be a potential catalyst for CO 2 activation and its coupling with epoxides.

Reactivity of a Sterical Flexible Pentabenzylcyclopentadienyl Samarocene

Reactivity studies of the classical divalent lanthanide compound [CpBz52Sm] (CpBz5 = pentabenzylcyclopentadienyl-anion) towards diphenyl dichalcogenides and d-element carbonyl complexes led to remarkable results. In the compounds obtained, a different number of Sm-C(phenyl) interactions and differently oriented benzyl groups were observed, suggesting—despite the preference of these interactions in [CpBz52Sm] described in previous studies—a flexible orientation of the benzyl groups and thus a variable steric shielding of the metal center by the ligand. The obtained compounds are either present as monometallic complexes (reduction of the dichalcogenides) or tetrametallic bridged compounds in the case of the d/f-element carbonyl complexes.

Immobilization mechanism of antimony by applying zirconium‐manganese oxide in soil

Antimony (Sb) accumulation in soil poses great potential risk to ecological environment, and its mobilization, transformation and bioavailability are controlled by its fractions and species. Hence, it is important to develop functional materials with both adsorption and oxidation that achieve detoxification and control the mobilization of Sb. In this study, the synthesized zirconium‑manganese oxide (ZrMn) could extremely promoted the transformation of antimonite [Sb(III)] to antimonate [Sb(V)], induced the bioavailable Sb shift to well-crystallized (hydr)oxides of Mn and residual fractions, and further reduced mobility and bioavailability Sb in soil. The sorption of ZrMn to Sb(III) and antimonate Sb(V) were affected by interfering ions, and to Sb(III) was a heterogeneous adsorption process. Spectroscopic characterization of XPS and FTIR suggested exchange between the hydroxyl groups and Sb was crucial in its retain and forming an electronegative inner-sphere mononuclear or binuclear bridging compound. The oxidation induced the transformation of Mn species in ZrMn, generated Mn(II) and Mn(III) exposing more reactive sites conducive to oxidation and adsorption, thus Mn oxides has a higher adsorption capacity for Sb(III). However, the Zr oxides of ZrMn presented adsorption rather than oxidation. The application of ZrMn could realize the dual effect of Sb oxidation detoxification and adsorption immobilization in soil, which provided references for Sb contaminated soil remediation.

Highly Enantioselective Michael Addition of Cyclic Diketones to β,γ-Unsaturated α-Keto Esters Catalyzed by Squaramide Organocatalyst

AbstractA new tertiary amine-squaramide organocatalyst has been developed and applied to the asymmetric Michael addition of cyclic diketones to β,γ-unsaturated α-keto esters. The catalyst system performed well with a low catalyst loading of 1 mol% under mild reaction conditions. A series of synthetically and pharmaceutically useful chiral bicyclic compounds were obtained in high yields (up to 97%) with excellent enantioselectivities (up to 99 % ee). Furthermore, this catalytic system can be used efficiently in large-scale reactions with the yields and enantioselectivities being maintained.

Thiazolopyrimidines: A Retrospective Study of Synthesis, Structure-Activity Relationship and Diverse Pharmacological Actions

Thiazolopyrimidine is a nitrogen and sulphur containing heterocyclic aromatic molecule. The bicyclic compound is made by fusing two aromatic rings, thiazole and pyrimidine and replacing one carbon atom with nitrogen and sulphur. The current present work covers a wide range of methods for synthesizing thiazolopyrimidine and its derivatives using a variety of catalysts, solvent medium and microwave irradiation with a goal of achieving a high yield and rapid separation of the product. This article describes the evolution of thiazolopyrimidine as antimicrobial, antiviral, anti-Parkinson, anticancer, anti-inflammatory as well as its structure-activity relationship and potential mode of action for future research. It also includes a list of current patents filed/granted linked to various pharmacological activities in the previous few years.

Beyond simple hetero Diels-Alder cycloadditions. A new type of element-ligand cooperativity at N,C,N-coordinated arsinidene and stibinidene centres in the reaction with an electron-deficient alkyne.

The reactivity of two types of organopnictogen(I) N,C,N-pincer ligand coordinated compound, i.e. [2,6-(DippNCH)2C6H3]E (1-E, where E = As, Sb, Bi; Dipp = 2,6-iPrC6H3) and [2-(DippNCH)-6-(DippNHCH2)C6H3]E (6-E, where E = As or Sb), toward an electron-deficient alkyne, i.e. dimethyl acetylenedicarboxylate (DMAD), is reported. All reactions represent remarkable examples of element-ligand cooperation (ELC). In the first step, all compounds react via dearomatization of a latent heteropnictole ring producing rare examples of hetero Diels-Alder (DA) adducts. These compounds then smoothly convert to 1-arsanaphthalenes via hydrogen migration, thereby recovering the aromatic 10π-electron system. Furthermore, in the case of bis(imino) derivatives of 1-E, heating of DA adducts in pyridine led to a hydrogenation of the triple bond of DMAD with the concomitant recovery of the univalent pnictinidene centre, which is in turn able to activate the second molecule of DMAD. In contrast, the non-symmetric derivative of 6-As upon heating in pyridine produced bicyclic trivalent arsenic compounds as a result of an attack of the pendant secondary NH group into the arsa-heterocyclic system. For 6-Sb, a remarkable stoichiometric hydrogenation of the DMAD molecule was observed by NMR spectroscopy involving the reductive elimination of dimethylfumarate in the final step of the reaction sequence. The whole study is accompanied by a theoretical survey that describes the main thermodynamic parameters of the reported reactions and explains the reaction pathways observed in the experiments.

A cyclic thioketone as biradical heterocyclopentane-1,3-diyl: synthesis, structure and activation chemistry

Reaction of [(μ-NR)P˙]2 with CSCl2 and Mg gives a deep blue, highly labile cyclic thioketone with singlet biradical character. It can be converted to a housane-type isomer by light and to bicyclic cage compounds by addition of CS2 and benzaldehyde.

NORBORNADIENO: SÍNTESE E APLICAÇÕES

NORBORNADIENE: SYNTHESIS AND APPLICATIONS. Bicyclo[2.2.1]hepta-2,5-diene or norbornadiene (NBD) is a bicyclic hydrocarbon molecule used in many fields of chemistry since its first synthesis in 1950. NBD is the precursor of Aldrin, an agrochemical that was commonly used as an insecticide until the end of the XX century. Norbornadiene is capable of interconverting into its isomer, quadricyclane (QC), by the incidence of ultraviolet light. After that, the QC can release heat to return to the initial stage of NBD. To increase the energy efficiency and to enable the reaction to occur at the solar light, chemists have synthesized a wide variety of NBD derivatives. Papers in more than seventy years have studied and reported the physical and chemical properties of those compounds and their applications as rocket fuel, solar energy cell, homogeneous catalysis, and agrochemicals published between 1950 and 2021. Even computational chemistry has been used to investigate the NBD derivatives synthetic routes, elucidation, and application. In addition, this review describes other applications of norbornadiene.

Study and quantification of the enantiodiscrimination power of four polymeric chiral LLCs using NAD 2D-NMR.

Identifying and understanding the role of key molecular factors involved in the orientation/discrimination phenomena of analytes in polymer-based chiral liquid crystals (CLCs) are essential tasks for optimizing computational predictions (molecular dynamics simulation) of the existing orienting systems, as well as designing novel helically chiral polymers as new enantiodiscriminating aligning media. From this perspective, we propose to quantify and compare the enantiodiscrimination power of four homochiral polymer-based lyotropic liquid crystals (LLCs) toward a given chiral solute using their 2H residual quadrupolar couplings (2H-RQCs) measured by anisotropic natural abundance deuterium 2D-NMR (ANAD 2D-NMR). Two families of chiral polymers are investigated in this study: (i) poly-peptide polymers (PBLG and PCBLL), and (ii) polyacetylene polymers (PDA and L-MSP, a new system never published so far). As model solute, we investigate the case of camphor, an interesting rigid bicyclic chiral molecule possessing ten 2H-RQCs (10 inequivalent monodeurated isotopomers per enantiomer). In order to analyse the orientational behaviour of each enantiomer in a single oriented sample, while simplifying the identification of the (D/L)-isomer signals on spectra, a D-isomer enriched scalemic mixture (ee(D) = 30%) was used. Orientational data of camphor in each mesophase were calculated for the first time using the computer program ConArch+, modified to accept 2H-RQCs as anisotropic data input. Differences in enantiodiscriminations provided by the four aligning systems are examined and discussed in terms of structural and chemical features between polymers. The new L-MSP mesophase described in this work exhibits very promising enantiodiscrimination capacities.