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The benzimidazole core (BI) plays a central role in biologically active molecules. The BI nucleus is widely used as a building block to generate a variety of bioactive heterocyclic compounds to be used as antihelmintics, antiprotozoal, antimalarials, anti-inflammatories, antivirals, antimicrobials, antiparasitics, and antimycobacterials. A versatile BI derivative is the 2-guanidinobenzimidazole (2GBI), which, together with its derivatives, is a very interesting poly-functional planar molecule having a delocalised 10 π electrons system conjugated with the guanidine group. The 2GBI molecule has five nitrogen atoms containing five labile N-H bonds, which interact with the out-ward-facing channel entrance, forming a labile complex with the biological receptor sites. In this work, 2GBI and their derivatives were analyzed as ligands to form host-guest, coordination and organometallic complexes. Synthesis methodology, metal geometries, hydrogen bonding (HB) interactions, and the biological activities of the complexes were discussed.

Ulcerative colitis (UC) is a multifactorial disease that causes long-lasting inflammation and ulcers in the digestive tract. UC is the most common form of inflammatory bowel disease (IBD). The current treatment for mild-to-moderate UC involves the use of 5-aminosalicylates (5-ASA), but much of this compound is unabsorbed and metabolized by N-acetylation. Several efforts have since been made to evaluate new molecules from synthetic or natural sources. Recently, it was reported that (E)-(5-chloro-2-hydroxy)-α-aminocinnamic acid (2c) and (E)-(2,4-dihydroxy)-α-aminocinnamic acid (2f) are as good or better myeloperoxidase (MPO) inhibitors and antioxidants than 5-ASA. Then, the present study aimed to evaluate the protective effects of 2c and 2f on a rat model of UC induced by 2,4,6-trinitrobenzene sulfonic acid (TNBS). The results showed that TNBS caused the induction of colonic ulcers, as well as a significant increase in MPO activity and malondialdehyde (MDA) and a decrease in glutathione (GSH) content. The administration of 2f, 2c and 5-ASA, decreased the ulcers presence, inhibited MPO peroxidation activity and MPO presence (as determined by immunofluorescence), and increased GSH and reduced MDA content. However, 2f was better than 2c and 5-ASA, then, the principal mechanism by which 2f presented a protective effect in a UC model induced by TNBS in rats is by inhibiting MPO activity and due to its antioxidant activity., (© 2024 The Author(s).)

Breast cancer (BC) is the most common cancer and the main cause of mortality due to cancer in women around the World. Histone deacetylase 6 (HDAC6) is a promising target for the treatment of BC. In the present study, a series of novel 3-carboxy-coumarin sulfonamides, analogs of belinostat, targeting HDAC6 were designed and synthesized. The compounds were synthesized and purified through open-column chromatography. Characterization was performed using spectroscopic techniques, including 1 H and 13 C NMR, homonuclear and heteronuclear correlation experiments, IR and UV. Molecular docking was carried out using AutoDock Vina implemented in UCSF Chimera version 1.16 against the HDAC6 protein structure (PDB: 5EDU). 2D protein-ligand interaction diagrams were generated with Maestro, and validation was conducted by redocking trichostatin A into the HDAC6 active site. Additionally, the compounds were evaluated in cancer cell lines (MDA-MB-231, MCF-7 and NIH/3T3), and healthy cells using lymphocytes from healthy volunteers. In the in vitro experiments, the compounds evaluated showed cytotoxic activity against the BC cell lines MCF-7 and MDA-MB-231 and the non-malignant cells 3T3/NIH. Compounds 5, 8a-c exhibited antiproliferative activity comparable to that of cisplatin and doxorubicin. Molecular docking studies showed that compounds with the 3-benzoylcoumarin scaffold had favorable affinity with catalytic domain of HDAC6 and whose interactions are similar to those found in belinostat. Compounds 5, 8b, 8c, 4c, and 8a exhibited higher viability against nonmalignant cells (leukocytes), with percentages ranging from 73-87%, demonstrating 3-4-fold lower potency than belinostat against healthy cells., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Madrigal-Angulo et al.)

Boronic acids form diester bonds with cis-hydroxyl groups in carbohydrates. The formation of these adducts could impair the physical and chemical properties of precursors, even their biological activity. Two carbohydrate derivatives from d-fructose and d-arabinose and phenylboronic acid were synthesized in a straightforward one-step procedure and chemically characterized via spectroscopy and X-ray diffraction crystallography. Additionally, an acute toxicity test was performed to determine their lethal dose 50 (LD 50 ) values by using Lorke's method. Analytical chemistry assays confirmed the formation of adducts by the generation of diester bonds with the β-d-pyranose of carbohydrates, including signals corresponding to the formation of new bonds, such as the stretching of B-O bonds. NMR spectra yielded information about the stereoselectivity in the synthesis reaction: Just one signal was found in the range for the anomeric carbon in the 13 C NMR spectra of both adducts. The acute toxicity tests showed that the LD 50 value for both compounds was 1265 mg/kg, while the effective dose 50 (ED 50 ) for sedation was 531 mg/kg. However, differences were found in the onset and lapse of sedation. For example, the arabinose derivative induced sedation for more than 48 h at 600 mg/kg, while the fructose derivative induced sedation for less than 6 h at the same dose without the death of the mice. Thus, we report for the first time two boron-containing carbohydrate derivatives inducing sedation after intraperitoneal administration. They are bioactive and highly safe agents. Further biological evaluation is desirable to explore their medical applications.

Flavonoids, a phenolic compounds class widely distributed in the plant kingdom, have attracted much interest for their implications on several health and disease processes. Usually, the consumption of this type of compounds is approximately 1 g/d, primarily obtained from cereals, chocolate, and dry legumes ensuring its beneficial role in maintaining the homeostasis of the human body. In this context, in cancer disease prominent data points to the role of flavonoids as adjuvant treatment aimed at the regression of the disease. GPER, an estrogen receptor on the cell surface, has been postulated as a probable orchestrator of the beneficial effects of several flavonoids through modulation/inhibition of various mechanisms that lead to cancer progression. Therefore, applying pocket and cavity protein detection and docking and molecular dynamics simulations (MD), we generate, from a cluster composed of 39 flavonoids, crucial insights into the potential role as GPER ligands, of Puerarin, Isoquercetin, Kaempferol 3-O-glucoside and Petunidin 3-O-glucoside, aglycones whose sugar moiety delimits a new described sugar-acceptor sub-cavity into the cavity binding site on the receptor, as well as of the probable activation mechanism of the receptor and the pivotal residues involved in it. Altogether, our results shed light on the potential use of the aforementioned flavonoids as GPER ligands and for further evaluations in in vitro and in vivo assays to elucidate their probable anti-cancer activity., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The study of a macromolecule derived from DPP and triphenylamine, (DPP-BisTPA) by computational chemistry, its synthesis by direct arylation, optical characterization (UV-Vis and fluorescence) and electrochemistry (cyclic voltammetry), as well as its evaluation as a generator of reactive oxygen species indirectly, through the degradation of uric acid. The results obtained by DFT using B3LYP/6-31G (d, p) and TD-DFT using CAM-B3LYP/6-31G (d, p) reveal values of energy levels of the first singlet and triplet excited state that indicate a possible intersystem crossover and the possible generation of reactive oxygen species by a type I mechanism. The compound presents an absorption region within the phototherapeutic window. The electrochemical bandgap is 1.64 eV which suggests a behavior as a semiconductor. DPP-BisTPa were processed as hemispherical nanoparticles with a size around 100 nm, and NPOs were evaluated as a photosensitizer with a ROS generation yield of 4% using a photodynamic therapy flashlight as the light source., (© 2024. The Author(s).)

In this work, the synthesis of BODIPY-phenyl-triazole labelled coumarins (BPhTCs) using a two-step approach is described. The influence of the BODIPY appending on the photophysical, electrochemical and thermal properties of the phenyl-triazole-coumarin precursors (PhTCs) was investigated. Band gap energies were measured by absorption spectroscopy (2.20 ± 0.02 eV in the solid and 2.35 ± 0.01 eV in solution) and cyclic voltammetry (2.10 ± 0.05 eV). The results are supported by DFT calculations confirming the presence of lowest LUMO levels that facilitate the electron injection and stabilize the electron transport. Their charge-transport parameters were measured in Organic Field-Effect Transistor (OFET) devices. BPhTCs showed an ambipolar transistor behavior with good n-type charge mobilities (10 -2 cm 2 V -1 s -1 ) allowing these derivatives to be employed as promising semiconducting crystalline and fluorescent materials with good thermal and air stability up to 250 °C., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Itzia Irene Padilla-Martinez reports financial support was provided by National Council on Science and Technology (CONACYT now CONAHCYT, National Council on Humanities, Science and Technology), Mexico. Norberto Farfan reports financial support was provided by National Council on Science and Technology, Mexico. Jose Emilio de la Cerda-Pedro reports financial support was provided by National Council on Science and Technology, Mexico. Oscar Javier Hernandez-Ortiz reports financial support was provided by National Council on Science and Technology, Mexico. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors. Published by Elsevier Ltd.)

According to WHO statistics, breast cancer (BC) disease represents about 2.3 million diagnosed and 685,000 deaths globally. Regarding histological classification of BC, the Estrogen (ER) and Progesterone (PR) receptors negative-expression cancer, named Triple-Negative BC (TNBC), represents the most aggressive type of this disease, making it a challenge for drug discovery. In this context, our research group, applying a well-established Virtual Screening (VS) protocol, in addition to docking and molecular dynamics simulations studies, yielded two ligands identified as 6 and 37 which were chemically synthesized and evaluated on MCF-7 and MDA-MB-231 cancer cell lines. Strikingly, 37 assayed on MDA-MB-231 (a TNBC cell model) depicted an outstanding value of 18.66 μM much lower than 65.67 μM yielded by Gossypol Bcl-2 inhibitor whose main disadvantage is to produce multiple toxic effects. Highlighted above, enforce the premise of the computational tools to find new therapeutic options against the most aggressive forms of breast cancer, as the results herein showed., (© 2023. Springer Nature Limited.)

(Thio)ureas ((T)Us) and benzothiazoles (BTs) each have demonstrated to have a great variety of biological activities. When these groups come together, the 2-(thio)ureabenzothizoles [(T)UBTs] are formed, improving the physicochemical as well as the biological properties, making these compounds very interesting in medicinal chemistry. Frentizole, bentaluron and methabenzthiazuron are examples of UBTs used for treatment of rheumatoid arthritis and as wood preservatives and herbicides in winter corn crops, respectively. With this antecedent, we recently reported a bibliographic review about the synthesis of this class of compounds, from the reaction of substituted 2-aminobenzothiazoles (ABTs) with iso(thio)cyanates, (thio)phosgenes, (thio)carbamoyl chlorides, 1,1'-(thio)carbonyldiimidazoles, and carbon disulfide. Herein, we prepared a bibliographic review about those features of design, chemical synthesis, and biological activities relating to (T)UBTs as potential therapeutic agents. This review is about synthetic methodologies generated from 1968 to the present day, highlighting the focus to transform (T)UBTs to compounds containing a range substituents, as illustrated with 37 schemes and 11 figures and concluded with 148 references. In this topic, the scientists dedicated to medicinal chemistry and pharmaceutical industry will find useful information for the design and synthesis of this interesting group of compounds with the aim of repurposing these compounds.

Benzimidazole (BI) and its derivatives are interesting molecules in medicinal chemistry because several of these compounds have a diversity of biological activities and some of them are even used in clinical applications. In view of the importance of these compounds, synthetic chemists are still interested in finding new procedures for the synthesis of these classes of compounds. Astemizole (antihistaminic), Omeprazole (antiulcerative), and Rabendazole (fungicide) are important examples of compounds used in medicinal chemistry containing BI nuclei. It is interesting to observe that several of these compounds contain 2-aminobenzimidazole (2ABI) as the base nucleus. The structures of 2ABI derivatives are interesting because they have a planar delocalized structure with a cyclic guanidine group, which have three nitrogen atoms with free lone pairs and labile hydrogen atoms. The 10-π electron system of the aromatic BI ring conjugated with the nitrogen lone pair of the hexocyclic amino group, making these heterocycles to have an amphoteric character. Synthetic chemists have used 2ABI as a building block to produce BI derivatives as medicinally important molecules. In view of the importance of the BIs, and because no review was found in the literature about this topic, we reviewed and summarized the procedures related to the recent methodologies used in the N-substitution reactions of 2ABIs by using aliphatic and aromatic halogenides, dihalogenides, acid chlorides, alkylsulfonic chlorides, carboxylic acids, esters, ethyl chloroformates, anhydrides, SMe-isothioureas, alcohols, alkyl cyanates, thiocyanates, carbon disulfide and aldehydes or ketones to form Schiff bases. The use of diazotized 2ABI as intermediate to obtain 2-diazoBIs was included to produce Nsubstituted 2ABIs of pharmacological interest. Some commentaries about their biological activity were included., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Since the interfacial binding strength and structural integrity have a strong influence on the active sites of nanocomposites, this study focused on exploring the structural and electronic properties at the interface between the implanted metal ion and host support. For this, nanocomposites of gold embedded in CeO 2 -ZrO 2 and CeO 2 -Al 2 O 3 matrices were fabricated, and their structural and morphological properties were investigated using ICP-OES, UV-vis, XRD, Raman, HRTEM, and high-resolution XPS studies and compared. From the results, it was found that the deposition of gold is highly favored over CeO 2 -ZrO 2 (3.99 atomic %) than CeO 2 -Al 2 O 3 (1.21 atomic %); however, the same amount of gold was used for the synthesis of both nanocomposites, as befits it. The HRTEM images of Au/CeO 2 -ZrO 2 displayed well-organized yarn textured particles with less than 5 nm size, which lacks in Au/CeO 2 -Al 2 O 3 . The reason for this less systematized and less Au embedding in the presence of alumina in CeO 2 -Al 2 O 3 was verified with the high-resolution XPS studies of both nanocomposites and an elevated binding energy due to the mobility of Au particles over CeO 2 -Al 2 O 3 was observed, while for Au/CeO 2 -ZrO 2 , a very small binding energy shift of gold states (Au 4f5/2 0.39; Au 4f7/2 0.17 eV) and the CeO 2 -ZrO 2 matrix that favored an increased intermolecular force between gold and the supporting host was observed. This agrees well with UV-vis electronic spectrum analysis, which revealed that the incorporation of gold nanoparticles narrowed the band gap more significantly in Au/CeO 2 -ZrO 2 (4.2 eV) than Au/CeO 2 -Al 2 O 3 (4.94 eV) suggesting the elevated electron transfer from the conduction band of CeO 2 -ZrO 2 to Au interfaces. In addition, XRD and Raman studies of Au/CeO 2 -ZrO 2 showed a pronounced phase transformation of Ce 4+ to Ce 3+ in the presence of homovalent Zr 4+ ions with an increased structural disorder in CeO 2 promoting the localized surface plasmon resonance (LSPR) in the lattice of CeO 2 -ZrO 2 , which was less detected in Au/CeO 2 -Al 2 O 3 due to the interference of less-desired γ-Al 2 O 3 phases. These characteristics of Au/CeO 2 -ZrO 2 ensured its performance as a promised photocatalyst for thioanisole degradation without using any harmful oxidants, and its stability towards different irradiation conditions, such as visible, ultraviolet, and solar light.

3-(4-Formylphenyl)-triazole-coumarin hybrid chromophores (FPhTCs) were synthesized in good yields, using a click chemistry protocol, and were also structurally characterized. Their photophysical, electrochemical and thermal properties were measured demonstrating that FPhTCs are luminescent in the blue-violet region of the electromagnetic spectrum, both in solution and the solid state. They showed an electrochemical band-gap values of 2.79 ± 0.08 eV, resistivity values between 10 4 and 10 5 Ω cm and are thermally stable up to 225 °C, properties that promise FPhTCs as good candidates for optoelectronic or imaging applications. Their solution and solid state photoluminescent properties are discussed and supported by theoretical calculations., Competing Interests: The authors declare no competing financial interest., (This journal is © The Royal Society of Chemistry.)

Benzimidazole is an important heterocyclic fragment, present in many biologically active compounds with a great variety of therapeutic purposes. Most of the benzimidazole activities are explained through the existence of 1,3-tautomeric equilibrium. As the binding affinity of each tautomer to a protein target depends on an established bioactive conformation, the effect of tautomers on the ligand protein binding mechanism is determinant. In this work, we searched and analyzed a series of reported 13 C-NMR spectra of benzazoles and benzazolidine-2-thiones with the purpose of estimating their tautomeric equilibrium. Herein, several approaches to determine this problem are presented, which makes it a good initial introduction to the non-expert reader. This chemical shift difference and C4/C7 signals of benzimidazolidine-2-thione and 1-methyl-2-thiomethylbenzimidazole as references were used in this work to quantitatively calculate, in solution, the pyrrole-pyridine tautomeric ratio in equilibrium. The analysis will help researchers to correctly assign the chemical shifts of benzimidazoles and to calculate their intracyclic or exocyclic tautomeric ratio as well as mesomeric proportion in benzimidazoles.

The (thio)urea and benzothiazole (BT) derivatives have been shown to have a broad spectrum of biological activities. These groups, when bonded, result in the 2-(thio)ureabenzothizoles (TBT and UBT), which could favor the physicochemical and biological properties. UBTs and TBTs are compounds of great importance in medicinal chemistry. For instance, Frentizole is a UBT derivative used for the treatment of rheumatoid arthritis and systemic lupus erythematosus. The UBTs Bentaluron and Bethabenthiazuron are commercial fungicides used as wood preservatives and herbicides in winter corn crops. On these bases, we prepared this bibliography review, which covers chemical aspects of UBTs and TBTs as potential therapeutic agents as well as their studies on the mechanisms of a variety of pharmacological activities. This work covers synthetic methodologies from 1935 to nowadays, highlighting the most recent approaches to afford UBTs and TBTs with a variety of substituents as illustrated in 42 schemes and 13 figures and concluded with 187 references. In addition, this interesting review is designed on chemical reactions of 2-aminobenzothiazoles (2ABTs) with (thio)phosgenes, iso(thio)cyanates, 1,1'-(thio)carbonyldiimidazoles [(T)CDI]s, (thio)carbamoyl chlorides, and carbon disulfide. This topic will provide information of utility for medicinal chemists dedicated to the design and synthesis of this class of compounds to be tested with respect to their biological activities and be proposed as new pharmacophores.

Intramolecular charge transfer (ICT) effects are responsible for the photoluminescent properties of coumarins. Hence, optical properties with different applications can be obtained by ICT modulation. Herein, four 3-acetyl-2 H -chromen-2-ones ( 1a - d ) and their corresponding fluorescent hybrids 3- (phenylhydrazone)-chromen-2-ones ( 2a - d ) were synthesized in 74-65% yields. The UV-Vis data were in the 295-428 nm range. The emission depends on the substituent in position C-7 bearing electron-donating groups. Compounds 1b - d showed good optical properties due to the D-π-A structural arrangement. In compounds 2a - d , there is a quenching effect of fluorescence in solution. However, in the solid, an increase is shown due to an aggregation-induced emission (AIE) effect given by the rotational restraints and stacking in the crystal. Computational calculations of the HOMO-LUMO orbitals indicate high absorbance and emission values of the molecules, and gap values represent the bathochromic effect and the electronic efficiency of the compounds. Compounds 1a - d and 2a - d are good candidates for optical applications, such as OLEDs, organic solar cells, or fluorescence markers.

The preset neurodegenerations in Alzheimer disease (AD) are due to several mechanisms such as amyloidogenic proteolysis, neuroinflammation, mitochondrial dysfunction, neurofibrillary tangles, cholinergic dysfunction, among others. The aim of this work was to develop multitarget molecules for the treatment of AD. Therefore, a family of 64 molecules was designed based on ligand structure pharmacophores able to inhibit the activity of beta secretase (BACE1) and acetylcholinesterase (AChE) as well as to avoid amyloid beta (Aβ1-42) oligomerization. The backbone of designed molecules consisted of a trisubstituted aromatic ring, one of the substituents was a heterocyclic amine (piperidine, morpholine, pyrrolidine or N-methyl pyrrolidine) separated from the aromatic system by three carbon atoms. The set of compounds was screened in silico employing molecular docking calculations and chemoinformatic analyses. Based on Gibbs free energy of binding, binding mode and in silico predicted toxicity results, three of the best candidates were selected, synthesized, and evaluated in vitro; F3S4-m, F2S4-m, and F2S4-p. All three compounds prevented Aβ1-42 aggregation (F3S4-m in 30.5%, F2S4-p in 42.1%, and F2S4-m in 60.9%). Additionally, inhibitory activity against AChE (ki 0.40 μM and 0.19 μM) and BACE1 (IC50 15.97 μM and 8.38 μM) was also observed for compounds F2S4-m and F3S4-m, respectively. Despite the BACE IC50 results demonstrated that all compounds are very less potent respect to peptidomimetic inhibitor (PI-IV IC50 3.20 nM), we can still say that F3S4-m is capable to inhibit AChE and BACE1., Competing Interests: The authors have declared that no competing interests exist.

Breast cancer (BC) is the most frequently diagnosed cancer and is the second-most common cause of death in women worldwide. Because of this, the search for new drugs and targeted therapy to treat BC is an urgent and global need. Histone deacetylase 6 (HDAC6) is a promising anti-BC drug target associated with its development and progression. In the present work, the design and synthesis of a new family of dihydropyrazole-carbohydrazide derivatives (DPCH) derivatives focused on HDAC6 inhibitory activity is presented. Computational chemistry approaches were employed to rationalize the design and evaluate their physicochemical and toxic-biological properties. The new family of nine DPCH was synthesized and characterized. Compounds exhibited optimal physicochemical and toxicobiological properties for potential application as drugs to be used in humans. The in silico studies showed that compounds with -Br, -Cl, and -OH substituents had good affinity with the catalytic domain 2 of HDAC6 like the reference compounds. Nine DPCH derivatives were assayed on MCF-7 and MDA-MB-231 BC cell lines, showing antiproliferative activity with IC 50 at μM range. Compound 2b showed, in vitro, an IC 50 value of 12 ± 3 µM on human HDAC6. The antioxidant activity of DPCH derivatives showed that all the compounds exhibit antioxidant activity similar to that of ascorbic acid. In conclusion, the DPCH derivatives are promising drugs with therapeutic potential for the epigenetic treatment of BC, with low cytotoxicity towards healthy cells and important antioxidant activity.

Preclinical and clinical evidence supports melatonin and its analogues as potential treatment for diseases involving cognitive deficit such as Alzheimer's disease. In this work, we evaluated by in silico studies a set of boron-containing melatonin analogues on MT1 and MT2 receptors. Then, we synthesized a compound (borolatonin) identified as potent agonist. After chemical characterization, its evaluation in a rat model with cognitive deficit showed that it induced ameliorative effects such as those induced by equimolar administration of melatonin in behavioral tests and in neuronal immunohistochemistry assays. Our results suggest the observed effects are by means of action on the melatonin system. Further studies are required to clarify the mechanism(s) of action, as the beneficial effects on disturbed memory by gonadectomy in male rats are attractive.

Compound 5-{[(2E)-3-bromo-3-carboxyprop-2-enoyl]amino}-2-hydroxybenzoic acid ( C1 ), a new 5-aminosalicylic acid (5-ASA) derivative, has proven to be an antioxidant in vitro and an anti-inflammatory agent in mice. The in vivo inhibition of myeloperoxidase was comparable to that of indomethacin. The aim of this study was to take another step in the preclinical evaluation of C1 by examining acute toxicity with the up-and-down OECD method and pharmacokinetic profiles by administration of the compound to Wistar rats through intravenous (i.v.), oral (p.o.), and intraperitoneal (i.p.) routes. According to the Globally Harmonized System, C1 belongs to categories 4 and 5 for the i.p. and p.o. routes, respectively. An RP-HPLC method for C1 quantification in plasma was successfully validated. Regarding the pharmacokinetic profile, the elimination half-life was approximately 0.9 h with a clearance of 24 mL/min after i.v. administration of C1 (50 mg/kg). After p.o. administration (50 mg/kg), the maximum plasma concentration was reached at 33 min, the oral bioavailability was about 77%, and the compound was amply distributed to all tissues evaluated. Therefore, C1 administered p.o. in rats is suitable for reaching the colon where it can exert its effect, suggesting an important advantage over 5-ASA and indomethacin in treating ulcerative colitis and Crohn's disease.

Nowadays, organic chemists are interested in the field of heterocyclic chemistry due to its use in the synthesis of a great variety of biologically active compounds. Heterocyclic compounds are widely found in nature and are essential for life. Among these, some natural nitrogen containing heterocyclic compounds have been used as chemotherapeutic agents. Their attachment to sugar molecules either as thioglycosides or as nucleosides analogues plays an important role in vital biological processes as well as in synthetic organic chemistry. Molecules containing benzothiazole (BT) nuclei are of this interesting class of compounds because some of them have been found to have a wide variety of biological activities. In this sense, we selected this topic to review and to then summarize the procedures related to the condensation reactions of o -aminothiophenoles (ATPs) as well as their disulfides with carboxylic acids, esters, orthoesters, acyl chlorides, amides, and nitriles. The condensation reactions with carbon dioxide (CO 2 ) are included. Conventional methods with the use of acid and metal catalysts as well as recent green techniques, such as microwave irradiation, the use of ionic liquids, and ultrasound (US) chemistry, which have proven to have many advantages, were found in the review.

Repurposing studies have identified several FDA-approved compounds as potential inhibitors of the intracellular domain of epidermal growth factor receptor 1 (EGFR) and human epidermal receptor 2 (HER2). EGFR and HER2 represent important targets for the design of new drugs against different types of cancer, and recently, differences in affinity depending on active or inactive states of EGFR or HER2 have been identified. In this study, we first identified FDA-approved compounds with similar structures in the DrugBank to lapatinib and gefitinib, two known inhibitors of EGFR and HER2. The selected compounds were submitted to docking and molecular dynamics MD simulations with the molecular mechanics generalized Born surface area approach to discover the conformational and thermodynamic basis for the recognition of these compounds on EGFR and HER2. These theoretical studies showed that compounds reached the ligand-binding site of EGFR and HER2, and some of the repurposed compounds did not interact with residues involved in drug resistance. An in vitro assay performed on two different breast cancer cell lines, MCF-7, and MDA-MB-23, showed growth inhibitory activity for these repurposed compounds on tumorigenic cells at micromolar concentrations. These repurposed compounds open up the possibility of generating new anticancer treatments by targeting HER2 and EGFR.

Myeloperoxidase (MPO) is an enzyme present in human neutrophils, whose main role is to provide defenses against invading pathogens. However, highly reactive oxygen species (ROS), such as HOCl, are generated from MPO activity, leading to chronic diseases. Herein, we report the microwave-assisted synthesis of a new series of stable ( E )-(2-hydroxy)-α-aminocinnamic acids, in good yields, which are structurally analogous to the natural products ( Z )-2-hydroxycinnamic acids. The radical scavenging activity (RSA), MPO inhibitory activity and cytotoxicity of the reported compounds were evaluated. The hydroxy derivatives showed the most potent RSA, reducing the presence of DPPH and ABTS radicals by 77% at 0.32 mM and 100% at 0.04 mM, respectively. Their mechanism of action was modeled with BDE OH , IP and ΔE H-L theoretical calculations at the B3LYP/6 - 31 + G(d,p) level. Compounds showed in vitro inhibitory activity of MPO with IC 50 values comparable to indomethacin and 5-ASA, but cytotoxicities below 15% at 100-200 µM. Docking calculations revealed that they reach the amino acid residues present in the distal cavity of the MPO active site, where both the amino and carboxylic acid groups of the α-aminopropenoic acid arm are structural requirements for anchoring. ( E )-2-hydroxy-α-aminocinnamic acids have been synthesized for the first time with a reliable method and their antioxidant properties demonstrated.

The implementation of chemo- and bioinformatics tools is a crucial step in the design of structure-based drugs, enabling the identification of more specific and effective molecules against cancer without side effects. In this study, three new compounds were designed and synthesized with suitable absorption, distribution, metabolism, excretion and toxicity (ADME-tox) properties and high affinity for the G protein-coupled estrogen receptor (GPER) binding site by in silico methods, which correlated with the growth inhibitory activity tested in a cluster of cancer cell lines. Docking and molecular dynamics (MD) simulations accompanied by a molecular mechanics/generalized Born surface area (MMGBSA) approach yielded the binding modes and energetic features of the proposed compounds on GPER. These in silico studies showed that the compounds reached the GPER binding site, establishing interactions with a phenylalanine cluster (F206, F208 and F278) required for GPER molecular recognition of its agonist and antagonist ligands. Finally, a 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay showed growth inhibitory activity of compounds 4 , 5 and 7 in three different cancer cell lines-MIA Paca-2, RCC4-VA and Hep G2-at micromolar concentrations. These new molecules with specific chemical modifications of the GPER pharmacophore open up the possibility of generating new compounds capable of reaching the GPER binding site with potential growth inhibitory activities against nonconventional GPER cell models.

11-Beta hydroxysteroid dehydrogenase type 1 (11β-HSD1) regulates cortisol levels mainly in adipose, hepatic and brain tissues. There is a relationship between the high activity of this enzyme and the development of obesity and metabolic disorders. The inhibition of 11β-HSD1 has been shown to attenuate the development of type 2 diabetes mellitus, insulin resistance, metabolic syndrome and other diseases mediated by excessive cortisol production. In this work, fifteen benzothiazole derivatives substituted with electron-withdrawing and electron-donating groups were designed to explore their affinity for 11β-HSD1 using in silico methods. The results show that (E)-5-((benzo[d]thiazol-2-ylimino)(methylthio)methylamino)-2-hydroxybenzoic acid (C1) has good physicochemical properties and favorable interactions with 11β-HSD1 through hydrogen bonding and hydrophobic interactions in the catalytic site formed by Y183, S170 and Y177. Furthermore, C1 was synthesized and evaluated in vitro and ex vivo using clobenzorex (CLX) as a reference drug in obese Zucker rats. The in vitro results showed that C1 was a better inhibitor of human 11β-HSD1 than CLX. The ex vivo assay results demonstrated that C1 was capable of reducing 11β-HSD1 overexpression in mesenteric adipose tissue. Therefore, C1 was able to decrease the activity and expression of 11β-HSD1 better than CLX.

A new organic salt of metformin, an antidiabetic drug, and N , N '-(1,4-phenylene)dioxalamic acid, was mechanochemically synthesized, purified by crystallization from solution and characterized by single X-ray crystallography. The structure revealed a salt-type crystal hydrate composed of one dicationic metformin unit, two monoanionic units of the acid and four water molecules, namely H 2 Mf(HpOXA) 2 ∙4H 2 O. X-ray powder, IR, 13 C-CPMAS, thermal and BET adsorption-desorption analyses were performed to elucidate the structure of the molecular and supramolecular structure of the anhydrous microcrystalline mesoporous solid H 2 Mf(HpOXA) 2 . The results suggest that their structures, conformation and hydrogen bonding schemes are very similar. To the best of our knowledge, the selective formation of the monoanion HpOXA - , as well as its structure in the solid, is herein reported for the first time. Regular O(δ-)∙∙∙C(δ), O(δ-)∙∙∙N + and bifacial O(δ-)∙∙∙C(δ)∙∙∙O(δ-) of n→π * charge-assisted interactions are herein described in H 2 MfA organic salts which could be responsible of the interactions of metformin in biologic systems. The results support the participation of n→π * charge-assisted interactions independently, and not just as a short contact imposed by the geometric constraint due to the hydrogen bonding patterns.

Being the base of several non-communicable diseases, including cancer, inflammation is a complex process generated by tissue damage or change in the body homeostatic state. Currently, the therapeutic treatment for chronic inflammation related diseases is based on the use of selective cyclooxygenase II enzyme, COX-2, inhibitors or Coxibs, which have recently regained attention giving their preventive role in colon cancer. Thus, the discovery of new molecules that selectively inhibit COX-2 and other inflammatory mediators is a current challenge in the medicinal chemistry field. 1-Phenylbenzimidazoles have shown potential COX inhibitory activity, because they can reproduce the interaction profile of known COX inhibitors. Therefore, in the present investigation a series of 1,2-diphenylbenzimidazoles (DPBI) with different aromatic substitutions in the para position were synthesized and their interaction with COX-2 and nitric oxide synthase, iNOS, was determined in silico, in vitro and in vivo. Compound 2-(4-bromophenyl)-1-(4-nitrophenyl)-1H-benzo[d]imidazole showed the best inhibition towards COX-2, while compounds N-(4-(2-(4-bromophenyl)-1H-benzo[d]imidazol-1-yl)phenyl)acetamide and N-(4-(2-(4-chlorophenyl)-1H-benzo[d]imidazol-1-yl)phenyl)acetamide diminished the production of NO in vitro. Additionally, they had a significant anti-inflammatory activity in vivo when given orally., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In the design of 1-phenylbenzimidazoles as model cyclooxygenase (COX) inhibitors, docking to a series of crystallographic COX structures was performed to evaluate their potential for high-affinity binding and to reproduce the interaction profile of well-known COX inhibitors. The effect of ligand-specific induced fit on the calculations was also studied. To quantitatively compare the pattern of interactions of model compounds to the profile of several cocrystallized COX inhibitors, a geometric parameter, denominated ligand-receptor contact distance (LRCD), was developed. The interaction profile of several model complexes showed similarity to the profile of COX complexes with inhibitors such as iodosuprofen, iodoindomethacin, diclofenac, and flurbiprofen. Shaping of high-affinity binding sites upon ligand-specific induced fit mostly determined both the affinity and the binding mode of the ligands in the docking calculations. The results suggest potential of 1-phenylbenzimidazole derivatives as COX inhibitors on the basis of their predicted affinity and interaction profile to COX enzymes. The analyses also provided insights into the role of induced fit in COX enzymes. While inhibitors produce different local structural changes at the COX ligand binding site, induced fit allows inhibitors in diverse chemical classes to share characteristic interaction patterns that ensure key contacts to be achieved. Different interaction patterns may also be associated with different inhibitory mechanisms., (© 2019 John Wiley & Sons, Ltd.)

In this investigation, the reaction of 2-dithiomethylcarboimidatebenzothiazole with a series of six chiral amino-acids was studied. The reaction proceeds through the isolable sodium salt of SMe-isothiourea carboxylates as intermediates, whose reaction with methyl iodide in stirring DMF as solvent affords SMe-isothiourea methyl esters. The presence of water in the reaction leads to the corresponding urea carboxylates as isolable intermediates, whose methyl esters were obtained. Finally, the urea N -methyl amide derivatives were isolated when SMe-isothiourea or urea methyl esters were reacted with methylamine in the presence of water. The structures of synthesized compounds were established by 1 H and 13 C nuclear magnetic resonance and the structures of SMe-isothiourea methyl esters derived from ( l )-glycine, ( l )-alanine, ( l )-phenylglycine, and ( l )-leucine, by X-ray diffraction analysis. This methodology allows to functionalize 2-aminobenzothiazole with SMe-isothiourea, urea, and methylamide groups derived from chiral amino acids to get benzothiazole derivatives containing coordination sites and hydrogen bonding groups. Further research on the biological activities of some of these derivatives is ongoing.

Bladder relaxation through drug administration is an interesting topic in medicinal and combinatorial chemistry. In fact, compounds targeting catecholamine receptors [dopamine receptors and beta-adrenergic receptors (βAR) expressed in the bladder] are among the compounds commonly employed for this purpose. In particular, recent investigations have tended to focus on the β 3 -adrenoceptor (β 3 AR) as a target in the treatment of urinary incontinence and other disorders. However, organoboron compounds have been suggested as potent and efficient agents on these drug targets. In this work, through a docking study, we identified the parameters that induce a theoretical improvement in the affinity and activity of the organoboron compounds on the catecholamine receptors expressed in the bladder. Then, the identified potential drug, a boron-containing dopa-derivative named DPBX-L-Dopa, was synthesized and characterized. This compound induces a relaxation on the smooth muscle of the rat bladder, behaving as a weak relaxant compared to isoproterenol but with similar efficacy to BRL377, a selective β 3 AR agonist. However, unexpectedly, this effect was not blocked by propranolol or haloperidol at the concentrations at which they are able to block the catecholamine receptors in bladder tissue. In view of these results, the effect of DPBX-L-Dopa compound on the alpha 1 adrenergic receptors (α 1 AR) of aorta of the rats was also explored; however, no response of the tissue to this compound was obtained. The possible mechanisms of the action of this compound were explored and are discussed further.

Dioxoisoindolines have been included as a pharmacophore group in diverse drug-like molecules with a wide range of biological activity. Various reports have shown that phthalimide derivatives are potent inhibitors of AChE, a key enzyme involved in the deterioration of the cholinergic system during the development of Alzheimer's disease. In the present study, 2-(2-(3,4-dimethoxyphenyl)ethyl)isoindoline-1,3-dione was synthesized, crystallized and evaluated as an AChE inhibitor. The geometric structure of the crystal and the theoretical compound (from molecular modeling) were analyzed and compared, finding a close correlation. The formation of the C6-H6···O19 interaction could be responsible for the non-negligible out of phenyl plane deviation of the C19 methoxy group, the O3 from the carbonyl group lead to C16-H16···O3 i intermolecular interactions to furnish C(9) and C(14) infinite chains within the (- 4 0 9) and (- 3 1 1) families of planes. Finally, the biological experiments reveal that the isoindoline-1,3-dione exerts a good competitive inhibition on AChE (Ki = 0.33-0.93 mM; 95% confidence interval) and has very low acute toxicity (LD 50  > 1600 mg/kg) compared to the AChE inhibitors currently approved for clinical use.

A detailed structural analysis of the benzimidazole nitroarenes 1-(4-nitrophenyl)-1H-1,3-benzimidazole, C 13 H 9 N 3 O 2 , (I), 1-(4-nitrophenyl)-2-phenyl-1H-1,3-benzimidazole, C 19 H 13 N 3 O 2 , (II), and 2-(3-methylphenyl)-1-(4-nitrophenyl)-1H-1,3-benzimidazole, C 20 H 15 N 3 O 2 , (III), has been performed. They are nonplanar structures whose crystal arrangement is governed by Csp 2 -H...A (A = NO 2 , N py and π) hydrogen bonding. The inherent complexity of the supramolecular arrangements of compounds (I) (Z' = 2) and (II) (Z' = 4) into tapes, helices and sheets is the result of the additional participation of π-π NO2 and n-π* (n = O and N py ; π* = Csp 2 and N NO2 ) interactions that contribute to the stabilization of the equi-energetic conformations adopted by each of the independent molecules in the asymmetric unit. In contrast, compound (III) (Z' = 1) is self-paired, probably due to the effect of the steric demand of the methyl group on the crystal packing. Theoretical ab initio calculations confirmed that the presence of the arene ring at the benzimidazole 2-position increases the rotational barrier of the nitrobenzene ring and also supports the electrostatic nature of the orthogonal ONO...Csp 2 and N py ...NO 2 interactions.

Oxidative stress is related to the pathogenesis and progress of several human diseases. NADPH oxidase (NOX), and mainly the NOX2 isoform, produces superoxide anions (O 2 • - ). To date, it is known that NOX2 can be inhibited by preventing the assembly of its subunits, p47phox and p22phox. In this work, we analyzed the binding to NOX2 of the apocynin dimer, diapocynin (C1), a known NOX2 inhibitor, and of 18 designed compounds (C2-C19) which have chemical relationships to C1, by in silico methods employing a p47phox structure from the Protein Data Bank (PDB code: 1WLP). C1 and six of the designed compounds were recognized in the region where p22phox binds to p47phox and makes π-π interactions principally with W193, W263, and Y279, which form an aromatic-rich region. C8 was chosen as the best compound according to the in silico studies and was synthesized and evaluated in vitro. C8 was able to prevent the production of reactive oxygen species (ROS) similar to C1. In conclusion, targeting the aromatic region of p47phox through π-interactions is important for inhibiting NOX activity., (© 2017 Deutsche Pharmazeutische Gesellschaft.)

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in the metabolism of lipids and carbohydrates. The exogenous ligands of these receptors are thiazolidinediones (TZDs), which are used to treat type 2 diabetes mellitus (DM2). However, drugs from this group produce adverse effects such as hepatic steatosis. Hence, the aim of this work was to design a set of small molecules that can activate the γ isoform of PPARs while minimizing the adverse effects. The derivatives were designed containing the polar head of TZD and an aromatic body, serving simultaneously as the body and tail. Two ligands were selected out of 130 tested. These compounds were synthesized in a solvent-free reaction and their physicochemical properties and toxicity were examined. Acute oral toxicity was determined by administering these compounds to female Wistar rats in increasing doses (as per the OECD protocol 425). The median lethal dose (LD50) of the compound substituted with a hydroxyl heteroatom was above 2000 mg/kg, and that of the compound substituted with halogens was 700-1400 mg/kg. The results suggest that the compounds can interact with PPARγ and elicit biological responses similar to other TZDs, but without showing adverse effects. The compounds will be subsequently evaluated in a DM2 animal model., (Copyright © 2017. Published by Elsevier Inc.)

The solventless synthesis of tris(pyrazolyl)phenylmethane ligands of formula C₆H₅C(Pz R2 )₃ (R = H, Me), starting from PhCCl₃ and 3,5-dimethylpyrazole (Pz Me2 ) or pyrazole (Pz) was performed. The sterically crowded C₆H₅C(Pz Me2 )₃ is thermally transformed into the bis(pyrazolyl)( p -pyrazolyl)phenylmethane ligand Pz Me2 -C₆H₄CH(Pz Me2 )₂. In this compound both Pz Me2 rings are linked through the N-atom to the methine C-atom. At higher temperatures, the binding mode of Pz Me2 changes from N1 to C4. All transformations occurred via quinonoid carbocation intermediates that undergo an aromatic electrophilic substitution on the 4-position of Pz Me2 . Reaction conditions were established to obtain five tris(pyrazolyl)phenylmethane ligands in moderate to good yields. ¹H- and 13 C-NMR spectroscopy and X-ray diffraction of single crystals support the proposed structures.

Since the neuraminidase (NA) enzyme of the influenza A virus plays a key role in the process of release of new viral particles from a host cell, it is often a target for new drug design. The emergence of NA mutations, such as H275Y, has led to great resistance against neuraminidase inhibitors, including oseltamivir and zanamivir. Hence, we herein designed a set of derivatives by modifying the amine and/or carboxylic groups of oseltamivir. After being screened for their physicochemical (Lipinski's rule) and toxicological properties, the remaining compounds were submitted to molecular and theoretical studies. The docking simulations provided insights into NA recognition patterns, demonstrating that oseltamivir modified at the carboxylic moiety and coupled with anilines had higher affinity and a better binding pose for NA than the derivatives modified at the amine group. Based on these theoretical studies, the new oseltamivir derivatives may have higher affinity to mutant variants and possibly to other viral subtypes. Accordingly, two compounds were selected for synthesis, which together with their respective intermediates were evaluated for their cytotoxicity and antiviral activities. Their biological activity was then tested in cells infected with the A/Puerto Rico/916/34 (H1N1) influenza virus, and virus yield reduction assays were performed. Additionally, by measuring neuraminidase activity with the neuraminidase assay kit it was found that the compounds produced inhibitory activity on this enzyme. Finally, the infected cells were analysed with atomic force microscopy (AFM), observing morphological changes strongly suggesting that these compounds interfered with cellular release of viral particles., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Boron is ubiquitous in nature, being an essential element of diverse cells. As a result, humans have had contact with boron containing compounds (BCCs) for a long time. During the 20th century, BCCs were developed as antiseptics, antibiotics, cosmetics and insecticides. Boric acid was freely used in the nosocomial environment as an antiseptic and sedative salt, leading to the death of patients and an important discovery about its critical toxicology for humans. Since then the many toxicological studies done in relation to BCCs have helped to establish the proper limits of their use. During the last 15 years, there has been a boom of research on the design and use of new, potent and efficient boron containing drugs, finding that the addition of boron to some known drugs increases their affinity and selectivity. This mini-review summarizes two aspects of BCCs: toxicological data found with experimental models, and the scarce but increasing data about the structure-activity relationship for toxicity and therapeutic use. As is the case with boron-free compounds, the biological activity of BCCs is related to their chemical structure. We discuss the use of new technology to discover potent and efficient BCCs for medicinal therapy by avoiding toxic effects., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

5-[(4-carboxybutanoyl)amino]-2-hydroxybenzoic acid (C2) is a novel synthetic derivative of 5-aminosalicylic acid (5-ASA), which is currently being evaluated ex vivo as an anti-inflammatory agent and has shown satisfactory results. This study aimed to obtain the pharmacokinetic profiles, tissue distribution and plasma protein binding of C2 in Wistar Rats. Additionally, an HPLC method was developed and validated to quantify C2 in rat plasma. The pharmacokinetic profiles of intragastric, intravenous and intraperitoneal administration routes at singles doses of 100, 50, and 100 mg/kg, respectively, were studied in Wistar rats. The elimination half-life of intravenously administered C2 was approximately 33 min. The maximum plasma level of C2 was reached approximately 24 min after intragastric administration, with a Cmax value of 2.5 g/mL and an AUCtot value of 157 μg min-1/mL; the oral bioavailability was approximately 13%. Following a single intragastric or oral dose (100 mg/kg), C2 was distributed and detected in all examined tissues (including the brain and colon). The results showed that C2 accumulates over time. The plasma protein binding results indicated that the unbound fraction of C2 at concentrations of 1 to 20 μg/mL ranged from 89.8% to 92.5%, meaning that this fraction of C2 is available to cross tissues. Finally, the blood-plasma partitioning (BP ratio) of C2 in rat plasma was 0.71 and 0.6 at concentrations of 5 and 10 μg/mL, respectively, which indicates that C2 is free in the plasmatic phase and not inside blood cells. The results of this study suggest that a fraction of the administered C2 dose is absorbed in the stomach, and the fraction that is not absorbed reaches the small intestine and colon. This distribution constitutes the main advantage of C2 compared with 5-ASA for the treatment of ulcerative colitis (UC) and Crohn's disease (CD).

Alzheimer's disease (AD) is a major neurodegenerative disorder more common in older adults. One of the leading AD hypotheses involves the amyloid beta (A) production, it is associated to oxidative stress, neuroinflammation, and neurovascular damage. The interaction of A with the blood vessel wall contributes to the disruption of the blood-brain barrier (BBB), allowing neutrophil infiltration containing the myeloperoxidase enzyme (MPO), which produces hypochlorous acid (HOCl) a potent oxidant. Also, MPO could be released from the microglia cells and interact with the amyloid beta plaques. This review aims to study the role of MPO in the progression of AD, in particular its contribution to oxidative stress and neuroinflammation. Furthermore, to explore the MPO-potential as AD-biomarker to evaluate the therapeutic potential of its inhibitors to mitigate the neurotoxicity. Finally, revise MPO inhibitors that could act as dual inhibitors acting on MPO and acetylcholinesterase and or another target involved in AD.

Epigenetic alterations are associated with cancer and their targeting is a promising approach for treatment of this disease. Among current epigenetic drugs, histone deacetylase (HDAC) inhibitors induce changes in gene expression that can lead to cell death in tumors. Valproic acid (VPA) is a HDAC inhibitor that has antitumor activity at mM range. However, it is known that VPA is a hepatotoxic drug. Therefore, the aim of this study was to design a set of VPA derivatives adding the arylamine core of the suberoylanilide hydroxamic acid (SAHA) with different substituents at its carboxyl group. These derivatives were submitted to docking simulations to select the most promising compound. The compound 2 (N-(2-hydroxyphenyl)-2-propylpentanamide) was the best candidate to be synthesized and evaluated in vitro as an anti-cancer agent against HeLa, rhabdomyosarcoma and breast cancer cell lines. Compound 2 showed a better IC 50 (μM range) than VPA (mM range) on these cancer cells. And also, 2 was particularly effective on triple negative breast cancer cells. In conclusion, 2 is an example of drugs designed in silico that show biological properties against human cancer difficult to treat as triple negative breast cancer.

The title compound, C12H13NO4, is one of the few examples that exhibits a syn conformation between the amide and ester carbonyl groups of the oxalyl group. This conformation allows the engagement of the amide H atom in an intramolecular three-centred hydrogen-bonding S(6)S(5) motif. The compound is self-assembled by C=O...C=O and amide-π interactions into stacked columns along the b-axis direction. The concurrence of both interactions seems to be responsible for stabilizing the observed syn conformation between the carbonyl groups. The second dimension, along the a-axis direction, is developed by soft C-H...O hydrogen bonding. Density functional theory (DFT) calculations at the B3LYP/6-31G(d,p) level of theory were performed to support the experimental findings.

The development of β2 adrenoceptor (β2AR) agonists is of increasing interest because of their wide-ranging applications in medicine, particularly for the treatment of pulmonary diseases. Regarding the relaxation of smooth muscle that lines airways of mammals, some boron-containing adducts have demonstrated greater potency and efficacy compared to well-known boron-free compounds. We herein report the design and synthesis as well as the chemical and pharmacological characterization of a new boron-containing compound: ((R)-6-((S)-2-(tert-butylammonio)-1-hydroxyethyl)-2-hydroxy-2-isobutyl-4H-benzo[d][1,3,2] dioxaborinin-2-uide). Compared to its precursor (salbutamol), this compound induced relaxation of smooth muscle in guinea pig tracheal rings with greater potency and efficacy (EC50⩽28.02nM). Theoretical studies suggest the potential selectivity of this boron containing compound on the orthosteric site of beta adrenoceptors and/or signaling pathways, as well as the importance of the tetracoordinated boron atom in its structure for binding recognition properties., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Intramolecular hydrogen bond (HB) formation was analyzed in the model compounds N-(2-benzoylphenyl)acetamide, N-(2-benzoylphenyl)oxalamate and N1,N2-bis(2-benzoylphenyl)oxalamide. The formation of three-center hydrogen bonds in oxalyl derivatives was demonstrated in the solid state by the X-ray diffraction analysis of the geometric parameters associated with the molecular structures. The solvent effect on the chemical shift of H6 [δH6(DMSO-d6)-δH6(CDCl3)] and Δδ(ΝΗ)/ΔT measurements, in DMSO-d6 as solvent, have been used to establish the energetics associated with intramolecular hydrogen bonding. Two center intramolecular HB is not allowed in N-(2-benzoylphenyl)acetamide either in the solid state or in DMSO-d6 solution because of the unfavorable steric effects of the o-benzoyl group. The estimated ΔHº and ΔSº values for the hydrogen bonding disruption by DMSO-d6 of 28.3(0.1) kJ·mol-1 and 69.1(0.4) J·mol-1·K-1 for oxalamide, are in agreement with intramolecular three-center hydrogen bonding in solution. In the solid, the benzoyl group contributes to develop 1-D and 2-D crystal networks, through C-H∙∙∙A (A = O, π) and dipolar C=O∙∙∙A (A = CO, π) interactions, in oxalyl derivatives. To the best of our knowledge, this is the first example where three-center hydrogen bond is claimed to overcome steric constraints.

The reactions of the benzimidazole nitrogen atoms and the exocyclic amino group of 2-aminobenzimidazole with CS2 in NaOH basic medium followed by methylation with methyl iodide was explored. With careful control of the stoichiometric quantities and addition sequences, this set of reactions allows the selective functionalization of the benzimidazole ring with N-dithiocarbamate, S-methyldithiocarbamate or dimethyl- dithiocarboimidate groups. The products were characterized by 1H-, 13C-NMR spectroscopy and three of them by X-ray diffraction analysis. The preferred isomers, tautomers and conformers were established.

Valproic acid (VPA) is extensively used as an anticonvulsive agent and as a treatment for other neurological disorders. It has been shown that VPA exerts an anti-proliferative effect on several types of cancer cells by inhibiting the activity of histone deacetylases (HDACs), which are involved in replication and differentiation processes. However, VPA has some disadvantages, among which are poor water solubility and hepatotoxicity. Therefore, the aim of the present study was to design and synthesize three derivatives of VPA to improve its physicochemical properties and anti-proliferative effects. For this purpose, the amino acids aspartic acid, glutamic acid and proline were added to the molecular structure of VPA. Docking and molecular dynamics simulations were used to determine the mode of recognition of these three derivatives by different conformations of HDAC8. This receptor was used as the specific target because of its high affinity for this type of substrate. The results demonstrate that, compared to VPA, the test compounds bind to different sites on the enzyme and that hydrogen bonds and hydrophobic interactions play key roles in this difference. The IC50 values of the VPA derivatives, experimentally determined using HeLa cells, were in the mM range. This result indicates that the derivatives have greater antiproliferative effects than the parent compound. Hence, these results suggest that these amino acid derivatives may represent a good alternative for anticancer treatment.

Despite great efforts to develop new therapeutic strategies against Alzheimer's disease (AD), the acetylcholinesterase inhibitors (AChEIs): donepezil, rivastigmine, and galantamine, have been used only as a palliative therapeutic approach. However, the pathogenesis of AD includes several factors such as cholinergic hypothesis, amyloid-β (Aβ) aggregation, and oxidative stress. For this reason, the design of compounds that target the genesis and progression of AD could offer a therapeutic benefit. We have designed a set of compounds (M-1 to M-5) with pharmacophore moieties to inhibit the release, aggregation, or toxicity of Aβ, act as AChEIs and have antioxidant properties. Once the compounds were designed, we analyzed their physicochemical parameters and performed docking studies to determine their affinity values for AChE, β-site amyloid-protein precursor cleaving enzyme 1 (BACE1), and the Aβ monomer. The best ligands, M-1 and M-4, were then synthesized, chemically characterized, and evaluated in vitro. The in vitro studies showed that these compounds inhibit AChE (M-1 Ki = 0.12 and M-4 Ki = 0.17 μM) and BACE1 (M-1 IC50 = 15.1 and M-4 IC50 = 15.4 nM). They also inhibit Aβ oligomerization and exhibit antioxidant activity. In addition, these compounds showed low cytotoxicity in microglial cells. For these reasons, they are promising for future use as drugs in AD mice transgenic models.

Molecules of 1,2-bis(4-bromophenyl)-1H-benzimidazole, C19H12Br2N2, (I), and 2-(4-bromophenyl)-1-(4-nitrophenyl)-1H-benzimidazole, C19H12BrN3O2, (II), are arranged in dimeric units through C-H...N and parallel-displaced π-stacking interactions favoured by the appropriate disposition of N- and C-bonded phenyl rings with respect to the mean benzimidazole plane. The molecular packing of the dimers of (I) and (II) arises by the concurrence of a diverse set of weak intermolecular C-X...D (X = H, NO2; D = O, π) interactions.

The title mol-ecular salt, C13H11N2O(+)·Cl(-)·H2O, crystallizes as a monohydrate. In the cation, the phenol and benzimidazole rings are almost coplanar, making a dihedral angle of 3.18 (4)°. The chloride anion and benzimidazole cation are linked by two N(+)-H⋯Cl(-) hydrogen bonds, forming chains propagating along [010]. These chains are linked through O-H⋯Cl hydrogen bonds involving the water mol-ecule and the chloride anion, which form a diamond core, giving rise to the formation of two-dimensional networks lying parallel to (10-2). Two π-π inter-actions involving the imidazolium ring with the benzene and phenol rings [centroid-centroid distances = 3.859 (3) and 3.602 (3) Å, respectively], contribute to this second dimension. A strong O-H⋯O hydrogen bond involving the water mol-ecule and the phenol substituent on the benzimidazole unit links the networks, forming a three-dimensional structure.

NOX (NADPH oxidase) plays an important role during several pathologies because it produces the superoxide anion (O2•-), which reacts with NO (nitric oxide), diminishing its vasodilator effect. Although different isoforms of NOX are expressed in ECs (endothelial cells) of blood vessels, the NOX2 isoform has been considered the principal therapeutic target for vascular diseases because it can be up-regulated by inhibiting the interaction between its p47phox (cytosolic protein) and p22phox (transmembrane protein) subunits. In this research, two ethers, 4-(4-acetyl-2-methoxy-phenoxy)-acetic acid (1) and 4-(4-acetyl-2-methoxy-phenoxy)-butyric acid (2) and two esters, pentanedioic acid mono-(4-acetyl-2-methoxy-phenyl) ester (3) and heptanedioic acid mono-(4-acetyl-2-methoxy-phenyl) ester (4), which are apocynin derivatives were designed, synthesized and evaluated as NOX inhibitors by quantifying O2•- production using EPR (electron paramagnetic resonance) measurements. In addition, the antioxidant activity of apocynin and its derivatives were determined. A docking study was used to identify the interactions between the NOX2's p47phox subunit and apocynin or its derivatives. The results showed that all of the compounds exhibit inhibitory activity on NOX, being 4 the best derivative. However, neither apocynin nor its derivatives were free radical scavengers. On the other hand, the in silico studies demonstrated that the apocynin and its derivatives were recognized by the polybasic SH3A and SH3B domains, which are regions of p47phox that interact with p22phox. Therefore this experimental and theoretical study suggests that compound 4 could prevent the formation of the complex between p47phox and p22phox without needing to be activated by MPO (myeloperoxidase), this being an advantage over apocynin.

In the title compound, C(24)H(36)N(6)O(6)·C(2)H(6)OS, the carbonyl groups are in an antiperiplanar conformation, with O=C-C=O torsion angles of 178.59 (15) and -172.08 (16)°. An intramolecular hydrogen-bonding pattern is depicted by four N-H...O interactions, which form two adjacent S(5)S(5) motifs, and an N-H...N interaction, which forms an S(6) ring motif. Intermolecular N-H...O hydrogen bonding and C-H...O soft interactions allow the formation of a meso-helix. The title compound is the first example of a helical 1,2-phenylenedioxalamide. The oxalamide traps one molecule of dimethyl sulfoxide through N-H...O hydrogen bonding. C-H...O soft interactions give rise to the two-dimensional structure.

In the title complex salt, [Ir(C(5)H(4)O)(C(16)H(22)N(6))(CO)](CF(3)O(3)S), the Ir(III) centre adopts a distorted octahedral geometry with a facial coordination of the tris(3,5-dimethyl-1H-pyrazol-1-yl)methane ligand. The C-C distances of the iridacycle are in agreement with its iridacyclohexa-2,5-dien-4-one nature, which presents a nonsymmetric boat-like conformation with the C-Ir-C vertex more bent than the C-C(=O)-C vertex. The supramolecular architecture is mainly directed by CO...CO and CO...π and Csp(3)-H...O interactions, the arrangement of which depends on the anion.