The Rise of Boron-Containing Compounds: Advancements in Synthesis, Medicinal Chemistry, and Emerging Pharmacology.

Boron-containing compounds (BCC) have emerged as important pharmacophores. To date, five BCC drugs (including boronic acids and boroles) have been approved by the FDA for the treatment of cancer, infections, and atopic dermatitis, while some natural BCC are included in dietary supplements. Boron's Lewis acidity facilitates a mechanism of action via formation of reversible covalent bonds within the active site of target proteins. Boron has also been employed in the development of fluorophores, such as BODIPY for imaging, and in carboranes that are potential neutron capture therapy agents as well as novel agents in diagnostics and therapy. The utility of natural and synthetic BCC has become multifaceted, and the breadth of their applications continues to expand. This review covers the many uses and targets of boron in medicinal chemistry.

Interactions of a boron-containing levodopa derivative on D2 dopamine receptor and its effects in a Parkinson disease model.

Levodopa is a cornerstone in Parkinson's disease treatment. Beneficial effects are mainly by binding on D2 receptors. Docking simulations of a set of compounds including well-known D2-ligands and a pool of Boron-Containing Compounds (BCC), particularly boroxazolidones with a tri/tetra-coordinated boron atom, were performed on the D2 Dopamine receptor (D2DR). Theoretical results yielded higher affinity of the compound DPBX, a Dopaboroxazolidone, than levodopa on D2DR. Essential interactions with residues in the third and sixth transmembrane domains of the D2DR appear to be crucial to induce and stabilize interactions in the active receptor state. Results from a motor performance evaluation of a murine model of Parkinson's disease agree with theoretical results, as DPBX showed similar efficacy to that of levodopa for diminishing MPTP-induced parkinsonism. This beneficial effect was disrupted with prior Risperidone (D2DR antagonist) administration, supporting the role of D2DR in the biological effect of DPBX. In addition, DPBX limited neuronal loss in substantia nigra in a similar manner to that of levodopa administration.

In silico and in vivo neuropharmacological evaluation of two γ-amino acid isomers derived from 2,3-disubstituted benzofurans, as ligands of GluN1-GluN2A NMDA receptor.

The GABAergic and glutamatergic neurotransmission systems are involved in seizures and other disorders of the central nervous system (CNS). Benzofuran derivatives often serve as the core in drugs used to treat such neurological disorders. The aim of this study was to synthesize new γ-amino acids structurally related to GABA and derived from 2,3-disubstituted benzofurans, analyze in silico their potential toxicity, ADME properties, and affinity for the GluN1-GluN2A NMDA receptor, and evaluate their potential activity and neuronal mechanisms in a murine model of pentylenetetrazol (PTZ)- and 4-aminopyridine (4-AP)-induced seizures. The in silico analysis evidenced a low risk of toxicity for the test compounds as well as the probability that they can cross the blood-brain barrier (BBB) to reach their targets in the CNS. According to docking simulations, these compounds bind at the active site of the NMDA glutamate receptor with high affinity. The in vivo assays demonstrated that 4 protects against 4-AP-induced seizure episodes, suggesting negative allosteric modulation (NAMs) at the glutamatergic NMDA receptor. Contrarily, 3 (the regioisomer of 4) and its racemic derivatives (cis-2,3-dihydrobenzofurans) were previously described to exacerbate such episodes, pointing to their positive allosteric modulation (PAMs) of the same receptor.

Synthesis, In Silico, and Biological Evaluation of a Borinic Tryptophan-Derivative That Induces Melatonin-like Amelioration of Cognitive Deficit in Male Rat.

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.

1-Boc-Piperidine-4-Carboxaldehyde Prevents Binge-Eating Behaviour and Anxiety in Rats.

BACKGROUND: Piperidines are biogenic amines studied mainly in toxicology because they were initially found as alkaloids from peppers and insect venoms. Piperidines are also produced in the human body, and their actions seem to be related to wakefulness/sleep and other cognitive phenomena. Piperidines have been minimally characterized for therapeutic applications. In this context, 1-Boc-piperidine-4-carboxaldehyde (1-Boc-piperidine) is a piperidine-derivative molecule with no mechanism of action reported, although its uses include the synthesis of GPR119 selective agonists that have been patented as anti-obesity drugs. OBJECTIVES: The aim of this work was to study the effects of 1-Boc-piperidine on binge-eating behaviour and anxiety in Wistar rats. METHODS: In experimental protocol 1, binge-eating behaviour was induced in animals that received pre-treatment (i.p.) with (i) vehicle (methanol 10%; 1 mL/kg), (ii) 1-Boc-piperidine (1 µmol kg-1), or (iii) 1-Boc-piperidine (10 µmol kg-1). In experimental protocol 2, mildly stressed animals were evaluated in the elevated plus maze under the acute effects of the pre-treatments applied in experimental protocol 1. RESULTS AND CONCLUSIONS: 1-Boc-piperidine decreased, in a dose-dependent manner, the intake of calories from a succulent hyper-caloric food in a binge-eating protocol in female rats, whereas the acute exposition to this piperidine exerted an anxiolytic effect in the male rat. In both effects, the mechanism of action remains to be characterized.

Identification of two arylimides as cholinesterase inhibitors and testing of propranolol addition on impaired rat memory.

Alzheimer's disease (AD) is clearly linked to the decline of acetylcholine (ACh) effects in the brain. These effects are regulated by the hydrolytic action of acetylcholinesterase (AChE). Therefore, a central palliative treatment of AD is the administration of AChE inhibitors although additional mechanisms are currently described and tested for generating advantageous therapeutic strategies. In this work, we tested new arylamides and arylimides as potential inhibitors of AChE using in silico tools. Then, these compounds were tested in vitro, and two selected compounds, C7 and C8, as well as propranolol showed inhibition of AChE. In addition, they demonstrated an advantageous acute toxicity profile compared to that of galantamine as a reference AChE inhibitor. in vivo evaluation of memory performance enhancement was performed in an animal model of cognitive disturbance with each of these compounds and propranolol individually as well as each compound combined with propranolol. Memory improvement was observed in each case, but without a significant additive effect with the combinations.

Cell-based assays and molecular dynamics analysis of a boron-containing agonist with different profiles of binding to human and guinea pig beta2 adrenoceptors.

The design of beta2 adrenoceptor (ß2AR) agonists is attractive because of their wide-ranging applications in medicine, and the details of agonist interactions with ß2AR are interesting because it is considered a prototype for G-protein coupled receptors. Preclinical studies for agonist development have involved biological assays with guinea pigs due to a similar physiology to humans. Boron-containing Albuterol derivatives (BCADs) designed as bronchodilators have improved potency and efficacy compared with their boron-free precursor on guinea pig ß2ARs (gpß2ARs), and two of the BCADs (BR-AEA and boronterol) conserve these features on cells expressing human ß2ARs (hß2ARs). The aim of this study was to test the BCAD Politerol on gpß2ARs and hß2ARs in vitro and in silico. Politerol displayed higher potency and efficacy on gpß2AR than on hß2AR in experimental assays, possible explanations are provided based on molecular modeling, and molecular dynamics simulations of about 0.25 µs were performed for the free and bound states adding up to 2 µs in total. There were slight differences, particularly in the role of the boron atom, in the interactions of Politerol with gpß2ARs and hß2ARs, affecting movements of transmembrane domains 5-7, known to be pivotal in receptor activation. These findings could be instrumental in the design of compounds selective for hß2ARs.

Design, synthesis and in vitro evaluation of a Dopa-organoboron compound that acts as a bladder relaxant through non-catecholamine receptors.

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 (ßAR) expressed in the bladder] are among the compounds commonly employed for this purpose. In particular, recent investigations have tended to focus on the ß3-adrenoceptor (ß3AR) 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 ß3AR 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 (α1AR) 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.

Insights on the role of boron containing moieties in the design of new potent and efficient agonists targeting the ß2 adrenoceptor.

The development of ß2 adrenoceptor (ß2AR) 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.

Boron-containing compounds as labels, drugs, and theranostic agents for diabetes and its complications.

Diabetes is a disease with a high global burden. Current strategies have failed to limit the advancement and impact of the disease. Successful early diagnosis and treatment will require the development of new agents. In this sense, boron-containing compounds have been reported as agents with the ability to reduce glycemia and lipidemia. They have also been used for labeling and measuring carbohydrates and other molecules linked to the initial stages of diabetes and its progression. In addition, certain boron compounds bind to molecules related to diabetes development and their biological activity in the regulation of elevated glycemia. Finally, it should be noted that some boron compounds appear to exert beneficial effects on diabetes complications such as accelerating wound healing while ameliorating pain in diabetic patients.

In silico identification of a biarylamine acting as agonist at human ß3 adrenoceptors and exerting BRL37344-like effects on mouse metabolism.

Human ß3-adrenoceptor (ß3AR) agonists were considered potential agents for the treatment of metabolic disorders. However, compounds tested as ß3AR ligands have shown marked differences in pharmacological profile in rodent and human species, although these compounds remain attractive as they were successfully repurposed for the therapy of urinary incontinence. In this work, some biarylamine compounds were designed and tested in silico as potential ß3AR agonists on 3-D models of mouse or human ß3ARs. Based on the theoretical results, we identified, synthesized and tested a biarylamine compound (polibegron). In CHO-K1 cells expressing the human ß3AR, polibegron and the ß3AR agonist BRL 37344 were partial agonists for stimulating cAMP accumulation (50 and 57% of the response to isoproterenol, respectively). The potency of polibegron was 1.71- and 4.5-fold higher than that of isoproterenol and BRL37344, respectively. These results indicate that polibegron acts as a potent, but partial, agonist at human ß3ARs. In C57BL/6N mice with obesity induced by a high-fat diet, similar effects of the equimolar intraperitoneal administration of polibegron and BRL37344 were observed on weight, visceral fat and plasma levels of glucose, cholesterol and triglycerides. Similarities and differences between species related to ligand-receptor interactions can be useful for drug designing.

One-Step Synthesis, Crystallography, and Acute Toxicity of Two Boron-Carbohydrate Adducts That Induce Sedation in Mice.

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 (LD50) values by using Lorke's method. Analytical chemistry assays confirmed the formation of adducts by the generation of diester bonds with the ß-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 13C NMR spectra of both adducts. The acute toxicity tests showed that the LD50 value for both compounds was 1265 mg/kg, while the effective dose 50 (ED50) 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.

Borolatonin limits cognitive deficit and neuron loss while increasing proBDNF in ovariectomised rats.

BACKGROUND: Borolatonin is a potential therapeutic agent for some neuronal diseases such as Alzheimer's disease (AD). Its administration exerts ameliorative effects such as those induced by the equimolar administration of melatonin in behavioral tests on male rats and in neuronal immunohistochemistry assays. OBJECTIVE: In this study, motivated by sex differences in neurobiology and the incidence of AD, the ability of borolatonin to induce changes in female rats was assessed. METHODS: Effects of borolatonin were measured by the evaluation of both behavioral and immunohistopathologic approaches; additionally, its ability to limit amyloid toxicity was determined in vitro. RESULTS: Surprisingly, behavioral changes were similar to those reported in male rats, but not those evaluated by immunoassays regarding neuronal survival; while pro-brain-derived neurotrophic factor (BDNF) immunoreactivity and the limitation of toxicity by amyloid in vitro were observed for the first time. CONCLUSION: Borolatonin administration induced changes in female rats. Differences induced by the administration of borolatonin or melatonin could be related to the differences in the production of steroid hormones in sex dependence. Further studies are required to clarify the possible mechanism and origin of differences in disturbed memory caused by the gonadectomy procedure between male and female rats.

Effectiveness of Omega-3 Fatty Acid Supplementation in Improving the Metabolic and Inflammatory Profiles of Mexican Adults Hospitalized with COVID-19.

BACKGROUND AND OBJECTIVES: The development of severe COVID-19 is related to the preexistence of comorbidities and an inadequate nutritional status. The latter is a critical factor for the development of infection and the progression of the disease. Notably, optimal nutrition impacts immune system function, as malnutrition is related to high cytokine levels in the late phase of the disease, correlating with a poor prognosis. In this sense, omega-3 fatty acids (O3FAs) have anti-inflammatory properties that may reduce morbidity and mortality from COVID-19 infection. O3FAs are linked to a better prognosis in COVID-19 patients. MATERIALS AND METHODS: In this randomized, double-blind clinical trial, we evaluate the administration of O3FAs to unvaccinated Mexican patients for two weeks starting after the first two hours of hospitalization. RESULTS: The findings support the notion that O3FAs (in a dose high enough to satisfy human physiological requirements in a short time, one capsule of 1.4 g O3FAs daily) exert a comprehensive multi-systemic modulatory influence, affecting inflammatory and metabolic pathways. Significant perturbations in biomarkers, including absolute neutrophil count, hematocrit, and platelet indices, underscore the compound's anti-inflammatory effect. Concurrently, the intervention modulates pivotal metabolic and hepatic parameters, attenuating cardiovascular risk profiles and expediting patient convalescence. These multifarious effects are likely orchestrated through intricate biochemical mechanisms and are subject to individual variations predicated on metabolic factors. CONCLUSIONS: The results of this trial support the notion that O3FA supplementation has beneficial effects on COVID-19 patients with moderate presentation by regulating metabolism and limiting inflammation.

Boron-containing compounds on neurons: Actions and potential applications for treating neurodegenerative diseases.

Boron-containing compounds (BCC) exert effects on neurons. After the expanding of both the identification and synthesis of new BCC, novel effects in living systems have been reported, many of these involving neuronal action. In this review, the actions of BCC on neurons are described; the effects have been inferred by boron deprivation or addition. Also, the effects can be related to those mediated by interaction on ionic channels, G-protein coupled receptors, or other receptors exerting modification on neuronal behavior. Additionally, BCC have exhibited effects by the modulation of inflammation or oxidative processes. BCC are expanding as drugs. Deprivation of boron sources from the diet shows the role of some natural BCC. However, the observations of several new synthesized compounds suggest their ability to act with attractive potency, efficacy, and long-term action on neuronal receptors or processes related with the origin and evolution of neurodegenerative processes. The details of BCC-target interactions are currently being elucidated in progress, as those observed from BCC-protein crystal complexes. Taking all of the above into account, the expansion is presumably near to having studies on the application of BCC as drugs on specific targets for treating neurodegenerative diseases.

Cell-based and in-silico studies on the high intrinsic activity of two boron-containing salbutamol derivatives at the human ß2-adrenoceptor.

Salbutamol is a well-known ß(2) adrenoceptor (ß(2)AR) partial agonist. We synthesized two boron-containing salbutamol derivatives (BCSDs) with greater potency and efficacy, compared to salbutamol, for inducing ß(2)AR-mediated smooth-muscle relaxation in guinea-pig tracheal rings. However, the mechanism involved in this pharmacological effect remains unclear. In order to gain insight, we carried out binding and functional assays for BCSDs in HEK-293T cells transfected with the human ß(2)AR (hß(2)AR). The transfected hß(2)AR showed similar affinity for BCSDs and salbutamol, but adenosine 3',5'-cyclic phosphate (cAMP) accumulation induced by both BCSDs was similar to that elicited by isoproterenol and greater than that induced by salbutamol. The boron-containing precursors (boric and phenylboronic acids, 100 µM) had no significant effect on salbutamol binding or salbutamol-induced cAMP accumulation. These experimental results are in agreement with theoretical docking simulations on lipid bilayer membrane-embedded hß(2)AR structures. These receptors showed slightly higher affinity for BCSDs than for salbutamol. An essential change between putative active and inactive conformational states depended on the interaction of the tested ligands with the fifth, sixth and seventh transmembrane domains. Overall, these data suggest that BCSDs induce and stabilize conformational states of the hß(2)AR that are highly capable of stimulating cAMP production.

Diversity of effects induced by boron-containing compounds on immune response cells and on antibodies in basal state.

BACKGROUND: It has been reported that boron induces changes in the immune response, including in inflammatory processes. Recently, the effect of boric acid has been documented on the differentiation of lymphocyte clusters in mice and rats. However, the differences among boron-containing compounds (BCC) have been poorly explored. METHODS: In this study, we analyzed the effects after oral administration of boric acid (BOR), methylboronic (MET), 3-thyenylboronic (3TB), 4-hydroxymethyl-phenylboronic (4MP) and 4-methanesulfonyl-phenylboronic (4SP) acids on the populations of lymphocytes from spleen and Peyer's patch (PP) as well as on antibodies. Groups of six male BALB/c were orally treated with 4.6 mg/kg of body weight with BOR, MET, 3TB, 4MP, and 4SP/daily for 10 days or vehicle (VEH) as a control group. After euthanasia, the spleen and small intestine were dissected. We conducted flow cytometry assays to assess B, CD3+ T, CD4+ T, and CD8+ T cells. Levels of IgG and IgM in serum, and IgA in intestinal fluid samples were analyzed by enzyme immunoassay. RESULTS: In particular, we observed the effects of the administration of boronic acids on the number of lymphocytes; these changes were more notable in spleen than in PP. We found different profiles for each boron-containing compound, that is BOR induced an increase in the percentage of CD8+ T and CD19+/IgA+ cells in spleen, but a decrease in CD8+ T and B220+/CD19+ cells in PP. Meanwhile MET induced a decrease of CD4+ T in spleen, but induced an increase of CD4+ T cells and a decrease in the number of CD8+ T cells in PP. Boronic acids with an aromatic ring moiety induced changes in serum immunoglobulins levels, while 3TB acid induced a notable increase in S-IgA. CONCLUSIONS: Effects in lymphocyte populations and antibodies are different for each tested compound. These results highlight the establishment of the necessary structure-activity relationship for BCC as immunomodulatory drugs. This is relevant in the biomedical field due to their attractiveness for selecting compounds to develop therapeutic tools.

Global longitudinal strain is superior to ejection fraction for detecting myocardial dysfunction in end-stage renal disease with hyperparathyroidism.

BACKGROUND: The estimation of left ventricular ejection fraction (LVEF) by 2D echocardiography (2D-ECHO) is the most used tool to assess LV systolic function (LVSF). Global longitudinal strain (GLS) has recently been suggested as a superior method for several evaluations. This study explored the association and prevalence of LV systolic dysfunction (LVSD) by using these methods in patients with end-stage renal disease (ESRD) and severe hyperparathyroidism (SHPTH); both associated with cardiovascular events (CEs). AIM: To evaluate the myocardial function in patients with ESRD and SHPTH by using the GLS and LVEF measured through conventional 2D-ECHO. METHODS: In 62 patients with ESRD and SHPTH, asymptomatic, and without a history of CEs, LVSF was evaluated by 2D-ECHO, obtaining the EF, by the Simpson biplane method, and GLS by speckle tracking. RESULTS: The total patients with ESRD had a preserved LVEF (> 50%) but abnormal GLS (< 13.55%). Additionally, multivariate analysis showed an independent association of GLS and serum parathyroid hormone (PTH), LV mass index, and hemoglobin. Also, PTH was independently associated with lateral e' wave and tricuspid regurgitation velocity. CONCLUSION: In patients with SHPTH linked to ESRD, the use of GLS by 2D-ECHO is a more sensitive tool than LVEF for detecting LVSD.

Polyphenols as potential enhancers of stem cell therapy against neurodegeneration.

The potential of polyphenols for treating chronic-degenerative diseases (particularly neurodegenerative diseases) is attractive. However, the selection of the best polyphenol for each treatment, the mechanisms by which they act, and their efficacy are frequently discussed. In this review, the basics and the advances in the field, as well as suggestions for using natural and synthetic polyphenols alone or in a combinatorial strategy with stem cell assays, are compiled and discussed. Thus, stem cells exhibit several responses when polyphenols are added to their environment, which could provide us with knowledge for advancing the elucidation of the origin of neurodegeneration. But also, polyphenols are being included in the innovative strategies of novel therapies for treating neurodegenerative diseases as well as metabolic diseases related to neurodegeneration. In this regard, flavonoid compounds are suggested as the best natural polyphenols due to their several mechanisms for acting in ameliorative effects; but increasing reports are involving other polyphenols. Even if some facts limiting bioactivity prevent them from conventional use, some natural polyphenols and derivatives hold the promise for being improved compounds, judged by their induced effects. The current results suggest polyphenols as enhancers of stem cell therapy against the targeted diseases.