Highly crystalline and fluorescent BODIPY-labelled phenyl-triazole-coumarins as n-type semiconducting materials for OFET devices.

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 cm2V-1s-1) allowing these derivatives to be employed as promising semiconducting crystalline and fluorescent materials with good thermal and air stability up to 250 °C.

Design, Synthesis and Biological Activities of (Thio)Urea Benzothiazole Derivatives.

(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.

N-substitution Reactions of 2-Aminobenzimidazoles to Access Pharmacophores.

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.

In Silico and In Vitro Studies of Benzothiazole-Isothioureas Derivatives as a Multitarget Compound for Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Inhibiting acetylcholinesterase (AChE), amyloid beta (Aß1-42) aggregation and avoiding the oxidative stress could prevent the progression of AD. Benzothiazole groups have shown neuroprotective activity whereas isothioureas groups act as AChE inhibitors and antioxidants. Therefore, 22 benzothiazole-isothiourea derivatives (3a-v) were evaluated by docking simulations as inhibitors of AChE and Aß1-42 aggregation. In silico studies showed that 3f, 3r and 3t had a delta G (ΔG) value better than curcumin and galantamine on Aß1-42 and AChE, respectively. The physicochemical and pharmacokinetics predictions showed that only 3t does not violate Lipinski's rule of five, though it has moderated cytotoxicity activity. Then, 3f, 3r and 3t were synthetized and chemically characterized for their in vitro evaluation including their antioxidant activity and their cytotoxicity in PC12 cells. 3r was able to inhibit AChE, avoid Aß1-42 aggregation and exhibit antioxidant activity; nevertheless, it showed cytotoxic against PC12 cells. Compound 3t showed the best anti-Aß1-42 aggregation and inhibitory AChE activity and, despite that predictor, showed that it could be cytotoxic; in vitro with PC12 cell was negative. Therefore, 3t could be employed as a scaffold to develop new molecules with multitarget activity for AD and, due to physicochemical and pharmacokinetics predictions, it could be administered in vivo using liposomes due to is not able to cross the BBB.

13C-NMR Chemical Shifts in 1,3-Benzazoles as a Tautomeric Ratio Criterion.

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 13C-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.

Synthesis and Biological Importance of 2-(thio)ureabenzothiazoles.

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.

Benzothiazoles from Condensation of o-Aminothiophenoles with Carboxylic Acids and Their Derivatives: A Review.

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 (CO2) 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.

Evaluation of the Antidiabetic and Antihyperlipidemic Activity of Spondias purpurea Seeds in a Diabetic Zebrafish Model.

Diabetes mellitus (DM) is a serious chronic degenerative disease characterized by high levels of glucose in the blood. It is associated with an absolute or relative deficiency in the production and/or action of insulin. Some of the complications associated with DM are heart disease, retinopathy, kidney disease, and neuropathy; therefore, new natural alternatives are being sought to control the disease. In this work, we evaluate the antidiabetic effect of Spondias purpurea seed methanol extract (CSM) in vitro and in a glucose-induced diabetic zebrafish model. CSM is capable of lowering blood glucose and cholesterol levels, as well as forming advanced glycation end-products, while not presenting toxic effects at the concentrations evaluated. These data show that CSM has a promising antidiabetic effect and may be useful in reducing some of the pathologies associated with diabetes mellitus.

Myeloperoxidase Inhibitory and Antioxidant Activities of (E)-2-Hydroxy-α-aminocinnamic Acids Obtained through Microwave-Assisted Synthesis.

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 BDEOH, IP and ΔEH-L theoretical calculations at the B3LYP/6 - 31 + G(d,p) level. Compounds showed in vitro inhibitory activity of MPO with IC50 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.

Mechanochemical Synthesis and Structure of the Tetrahydrate and Mesoporous Anhydrous Metforminium(2+)-N,N'-1,4-Phenylenedioxalamic Acid (1:2) Salt: The Role of Hydrogen Bonding and n→π * Charge Assisted Interactions.

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 H2Mf(HpOXA)2∙4H2O. X-ray powder, IR, 13C-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 H2Mf(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 H2MfA 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.

Anti-inflammatory effect and inhibition of nitric oxide production by targeting COXs and iNOS enzymes with the 1,2-diphenylbenzimidazole pharmacophore.

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.

Crystal structure of a new polymorph of 3-acetyl-8-meth-oxy-2H-chromen-2-one.

A new polymorphic form of the title compound, C12H10O4, is described in the ortho-rhom-bic space group Pbca and Z = 8, as compared to polymorph I, which crystallizes in the monoclinic space group C2/c and Z = 8 [Li et al. (2012). Chin. J. Struct. Chem. 31, 1003-1007.]. In polymorph II, the coumarin ring system is almost planar (r.m.s. deviation = 0.00129 Å). In the crystal, mol-ecules are connected by Csp 3-H⋯O and Car-H⋯O hydrogen bonds, forming mol-ecular sheets linked into zigzag shaped layers along the b-axis direction. The three-dimensional lattice is assembled through stacking of the zigzag layers by π-π inter-actions with a centroid-to-centroid distance of 3.600 (9) Šand anti-parallel C=O⋯C=O inter-actions with a distance of 3.1986 (17) Å, which give rise to a helical supra-molecular architecture.

Isothioureas, Ureas, and Their N-Methyl Amides from 2-Aminobenzothiazole and Chiral Amino Acids.

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 1H and 13C 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.

Involvement of conformational isomerism in the complexity of the crystal network of 1-(4-nitrophenyl)-1H-1,3-benzimidazole derivatives driven by C-H...A (A = NO2, Npy and π) and orthogonal Npy...NO2 and ONO...Csp2 interactions.

A detailed structural analysis of the benzimidazole nitroarenes 1-(4-nitrophenyl)-1H-1,3-benzimidazole, C13H9N3O2, (I), 1-(4-nitrophenyl)-2-phenyl-1H-1,3-benzimidazole, C19H13N3O2, (II), and 2-(3-methylphenyl)-1-(4-nitrophenyl)-1H-1,3-benzimidazole, C20H15N3O2, (III), has been performed. They are nonplanar structures whose crystal arrangement is governed by Csp2-H...A (A = NO2, Npy 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-πNO2 and n-π* (n = O and Npy; π* = Csp2 and NNO2) 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...Csp2 and Npy...NO2 interactions.

Solventless Synthesis of Poly(pyrazolyl)phenyl-methane Ligands and Thermal Transformation of Tris(3,5-dimethylpyrazol-1-yl)phenylmethane.

The solventless synthesis of tris(pyrazolyl)phenylmethane ligands of formula C6H5C(PzR2)3 (R = H, Me), starting from PhCCl3 and 3,5-dimethylpyrazole (PzMe2) or pyrazole (Pz) was performed. The sterically crowded C6H5C(PzMe2)3 is thermally transformed into the bis(pyrazolyl)(p-pyrazolyl)phenylmethane ligand PzMe2-C6H4CH(PzMe2)2. In this compound both PzMe2 rings are linked through the N-atom to the methine C-atom. At higher temperatures, the binding mode of PzMe2 changes from N1 to C4. All transformations occurred via quinonoid carbocation intermediates that undergo an aromatic electrophilic substitution on the 4-position of PzMe2. Reaction conditions were established to obtain five tris(pyrazolyl)phenylmethane ligands in moderate to good yields. ¹H- and 13C-NMR spectroscopy and X-ray diffraction of single crystals support the proposed structures.

Aminosilanes derived from 1H-benzimidazole-2(3H)-thione.

Two new molecular structures, namely 1,3-bis(trimethylsilyl)-1H-benzimidazole-2(3H)-thione, C13H22N2SSi2, (2), and 1-trimethylsilyl-1H-benzimidazole-2(3H)-thione, C10H14N2SSi, (3), are reported. Both systems were derived from 1H-benzimidazole-2(3H)-thione. Noncovalent C-H···π interactions between the centroid of the benzmidazole system and the SiMe3 groups form helicoidal arrangements in (2). Dimerization of (3) results in the formation of R2(2)(8) rings via N-H···S interactions, along with parallel π-π interactions between imidazole and benzene rings.

Carbonyl-carbonyl interactions and amide π-stacking as the directing motifs of the supramolecular assembly of ethyl N-(2-acetylphenyl)oxalamate in a synperiplanar conformation.

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.

Synthesis and structure of sulfur derivatives from 2-aminobenzimidazole.

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.

Solid state structure and solution thermodynamics of three-centered hydrogen bonds (O∙∙∙H∙∙∙O) using N-(2-benzoyl-phenyl) oxalyl derivatives as model compounds.

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.

Ameliorative Effect of Hexane Extract of Phalaris canariensis on High Fat Diet-Induced Obese and Streptozotocin-Induced Diabetic Mice.

Obesity is one of the major factors to increase various disorders like diabetes. The present paper emphasizes study related to the antiobesity effect of Phalaris canariensis seeds hexane extract (Al-H) in high-fat diet- (HFD-) induced obese CD1 mice and in streptozotocin-induced mild diabetic (MD) and severely diabetic (SD) mice.AL-H was orally administered to MD and SD mice at a dose of 400 mg/kg once a day for 30 days, and a set of biochemical parameters were studied: glucose, cholesterol, triglycerides, lipid peroxidation, liver and muscle glycogen, ALP, SGOT, SGPT, glucose-6-phosphatase, glucokinase, hexokinase, SOD, CAT, GSH, GPX activities, and the effect on insulin level. HS-H significantly reduced the intake of food and water and body weight loss as well as levels of blood glucose, serum cholesterol, triglyceride, lipoprotein, oxidative stress, showed a protective hepatic effect, and increased HDL-cholesterol, serum insulin in diabetic mice. The mice fed on the high-fat diet and treated with AL-H showed inhibitory activity on the lipid metabolism decreasing body weight and weight of the liver and visceral adipose tissues and cholesterol and triglycerides in the liver. We conclude that AL-H can efficiently reduce serum glucose and inhibit insulin resistance, lipid abnormalities, and oxidative stress in MD and SD mice. Our results demonstrate an antiobesity effect reducing lipid droplet accumulation in the liver, indicating that its therapeutic properties may be due to the interaction plant components soluble in the hexane extract, with any of the multiple targets involved in obesity and diabetes pathogenesis.