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Continuous efforts are being directed toward the employment of boron in drug design due to its advantages and unique characteristics including a plethora of target engagement modes, lower metabolism, and synthetic accessibility, among others. Phosphates are components of multiple drug molecules as well as clinical candidates, since they play a vital role in various biochemical functions, being components of nucleotides, energy currency- ATP as well as several enzyme cofactors. This review discusses the unique chemistry of boron functionalities as phosphate bioisosteres - "the boron-phosphorus elemental exchange strategy" as well as the superiority of boron groups over other commonly employed phosphate bioisosteres. Boron phosphate-mimetics have been utilized for the development of enzyme inhibitors as well as novel borononucleotides. Both the boron functionalities described in this review-boronic acids and benzoxaboroles-contain a boron connected to two oxygens and one carbon atom. The boron atom of these functional groups coordinates with a water molecule in the enzyme site forming a tetrahedral molecule which mimics the phosphate structure. Although boron phosphate-mimetic molecules - FDA-approved Crisaborole and phase II/III clinical candidate Acoziborole are products of the boron-phosphorus bioisosteric elemental exchange strategy, this technique is still in its infancy. The review aims to promote the use of this strategy in future medicinal chemistry projects.

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Benzoxaboroles are a new class of leucyl-tRNA synthetase inhibitors. Epetraborole, a benzoxaborole, is a clinical candidate developed for Gram-negative infections and has been confirmed to exhibit favorable activity against a well known pulmonary pathogen, Mycobacterium abscessus. However, according to ClinicalTrials.gov, in 2017, a clinical phase II study on the use of epetraborole to treat complicated urinary tract and intra-abdominal infections was terminated due to the rapid emergence of drug resistance during treatment. Nevertheless, epetraborole is in clinical development for nontuberculous mycobacteria (NTM) disease especially for Mycobacterium avium complex-related pulmonary disease (MAC-PD). DS86760016, an epetraborole analog, was further demonstrated to have an improved pharmacokinetic profile, lower plasma clearance, longer plasma half-life, and higher renal excretion than epetraborole in animal models. In this study, DS86760016 was found to be similarly active against M. abscessus in vitro, intracellularly, and in zebrafish infection models with a low mutation frequency. These results expand the diversity of druggable compounds as new benzoxaborole-based candidates for treating M. abscessus diseases.

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OBJECTIVE: The cleavage and polyadenylation endonuclease CPSF73 is thought to be the target of the anti-trypanosomal benzoxaboroles AN7973, acoziborole and AN11736. We previously showed that AN7973 inhibits mRNA processing. We here investigated whether the drug candidates acoziborole (for human sleeping sickness) and AN11736 (for nagana in cattle) have the same effect. We also affinity purified tagged CPSF73 from parasites without, or after, AN7973 treatment, and analysed differentially co-purified proteins by mass spectrometry. RESULTS: AN11736 and acoziborole both inhibited mRNA processing, as demonstrated by decreased levels of spliced mRNAs and accumulation of di- and tri-cistronic mRNAs from the alpha-beta tubulin locus. Treating the cells with AN7973 for 30 min. did not significantly affect the proteins that copurified with CPSF73.

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The incorporation of the "magic" boron atom has been established as an important new strategy in the field of medicinal chemistry as boron compounds have been shown to form various bonds with their biological targets. Currently, a number of boron-based drugs (e.g. bortezomib, crisaborole, and tavaborole) have been FDA approved and are in the clinic, and several other boron-containing compounds are in clinical trials. Boron-based heterocycles have an incredible potential in the ongoing quest for new therapeutic agents owing to their plethora of biological activities and useful pharmacokinetic profiles. The present perspective is intended to review the pharmacological applications of boron-based heterocycles that have been published. We have classified these compounds into groups exhibiting shared pharmacological activities and discussed their corresponding biological targets focusing mainly on the most potent therapeutic compounds.

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In this review, the history of boron's early use in drugs, and the history of the use of boron functional groups in medicinal chemistry applications are discussed. This includes diazaborines, boronic acids, benzoxaboroles, boron clusters, and carboranes. Furthermore, critical developments from these functional groups are highlighted along with recent developments, which exemplify potential prospects. Lastly, the application of boron in the form of a prodrug, softdrug, and as a nanocarrier are discussed to showcase boron's emergence into new and exciting fields. Overall, we emphasize the evolution of organoboron therapeutic agents as privileged structures in medicinal chemistry and outline the impact that boron has had on drug discovery and development.

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Mycobacterium abscessus is the one of the most feared bacterial respiratory pathogens in the world. Unfortunately, there are many problems with the current M. abscessus therapies available. These problems include misdiagnoses, high drug resistance, poor long-term treatment outcomes, and high costs. Until now, there have only been a few new compounds or drug formulations which are active against M. abscessus, and these are present in preclinical and clinical development only. With that in mind, new and more powerful anti-M. abscessus medicines need to be discovered and developed. In this study, we conducted an in vitro-dual screen against M. abscessus rough (R) and smooth (S) variants using a Pandemic Response Box and identified epetraborole as a new effective candidate for M. abscessus therapy. For further validation, epetraborole showed significant activity against the growth of the M. abscessus wild-type strain, three subspecies, drug-resistant strains and clinical isolates in vitro, while also inhibiting the growth of M. abscessus that reside in macrophages without cytotoxicity. Furthermore, the in vivo efficacy of epetraborole in the zebrafish infection model was greater than that of tigecycline. Thus, we concluded that epetraborole is a potential anti-M. abscessus candidate in the M. abscessus drug search.

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Benzoxaboroles emerged recently as molecules of high medicinal potential with Kerydin® (Tavaborole) and Eucrisa® (Crisaborole) currently in clinical practice as antifungal and anti-inflammatory drugs, respectively. Over a dozen of 3-amino benzoxaboroles, including Tavaborole's derivatives, have been synthetized and characterized in terms of their activity against Candida albicans as a model pathogenic fungus. The studied compounds broaden considerably the structural diversity of reported benzoxaboroles, enabling determination of the influence of the introduction of a heterocyclic amine, a fluorine substituent as well as the formyl group on antifungal activity of those compounds. The determined zones of the growth inhibition of examined microorganism indicate high diffusion of majority of the studied compounds within the applied media as well as their reasonable activity. The Minimum Inhibitory Concentration (MIC) values show that the introduction of an amine substituent in position "3" of the benzoxaborole heterocyclic ring results in a considerable drop in activity in comparison with Tavaborole (AN2690) as well as unsubstituted benzoxaborole (AN2679). In all studied cases the presence of a fluorine substituent at position para to the boron atom results in lower MIC values (higher activity). Interestingly, introduction of a fluorine substituent in the more distant piperazine phenyl ring does not influence MIC values. As determined by X-ray studies, introduction of a formyl group in proximity of the boron atom results in a considerable change of the boronic group geometry. The presence of a formyl group next to the benzoxaborole unit is also detrimental for activity against Candida albicans.

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Autotaxin (ATX) is an extracellular enzyme that hydrolyses lysophosphatidylcholine (LPC) to lysophosphatidic acid (LPA), which has a role in the mediation of inflammation, fibrosis and cancer. ATX is a drug target that has been the focus of many research groups during the last ten years. To date, only one molecule, Ziritaxestat (GLPG1690) has entered the clinic; it is currently in Phase 3 clinical trials for idiopathic pulmonary fibrosis. Other small molecules, with different binding modes, have been investigated as ATX inhibitors for cancer including compounds possessing a boronic acid motif such as HA155. In this work, we targeted new, improved inhibitors of ATX that mimic the important interactions of boronic acid using a benzoxaborole motif as the acidic warhead. Furthermore, we aimed to improve the plasma stability of the new compounds by using a more stable core spacer than that embedded in HA155. Compounds were synthesized, evaluated for their ATX inhibitory activity and ADME properties in vitro, culminating in a new benzoxaborole compound, 37, which retains the ATX inhibition activity of HA155 but has improved ADME properties (plasma protein binding, good kinetic solubility and rat/human plasma stability).

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Advances in the field of boron chemistry have expanded the application of this element in Medicinal Chemistry. Boron-containing compounds represent a new class for medicinal chemists to use in their drug designs. Bortezomib (Velcade®), a dipeptide boronic acid approved by the FDA in 2003 for treatment of multiple myeloma, paved the way for the discovery of new boron-containing compounds. After its approval, two other boron-containing compounds have been approved, tavaborole (Kerydin®) for the treatment of onychomicosis and crisaborole (Eucrisa®) for the treatment of mild to moderate atopic dermatitis. A number of boron-containing compounds have been described and evaluated for a plethora of therapeutic applications. The present review is intended to highlight the recent advances related to boron-containing compounds and their therapeutic applications. Here, we focused only in those most biologically active compounds with proven in vitro and/or in vivo efficacy in the therapeutic area published in the last years.

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Benzoxaborole is a series of compounds with five member ring and boron atom. Since the approval of crisaborole and tavaborole by FDA, benzoxaborole gained lots of research interests and become widely used in current drug discovery. Specially, benzoxaborole derivatives were found to exhibit anti-bacterial, anti-fungal, anti-protozoal, anti-tumor and anti-inflammatory activities. Here, we will review the properties of benzoxaborole, structure activity relationships as well as the recent progress in the biological activity of benzoxaborole derivatives.

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Due to the increased interest in their application in the treatment of infectious diseases, boron-containing compounds have received a significant coverage in the literature. Herein, a small set of novel cinnamoly-oxaborole amides were synthesized and screened against nagana Trypanosoma brucei brucei for antitrypanosomal activity. Compound 5g emerged as a new hit with an in vitro IC50 value of 0.086 µM against T. b. brucei without obvious inhibitory activity against HeLa cell lines. The same series was also screened against other human pathogens, including Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), for which moderate to weak activity (10 to >125 µM) was observed. Similarly, these compounds exhibited moderate activity against the human protozoal pathogen Trichomonas vaginalis with no observed effect on common microbiome bacterial species. The cross-species inhibitory activity presents the possibility of these compounds serving as broad-spectrum antibiotics for these prevalent three human pathogens.

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Cutaneous leishmaniasis (CL) is caused by several species of the protozoan parasite Leishmania, affecting an estimated 10 million people worldwide. Previously reported strategies for the development of topical CL treatments have focused primarily on drug permeation and formulation optimization as the means to increase treatment efficacy. Our approach aims to identify compounds with antileishmanial activity and properties consistent with topical administration. Of the test compounds, five benzoxaboroles showed potent activity (50% effective concentration [EC50] < 5 µM) against intracellular amastigotes of at least one Leishmania species and acceptable activity (20 µM < EC50 < 30 µM) against two more species. Benzoxaborole compounds were further prioritized on the basis of the in vitro evaluation of progression criteria related to skin permeation, such as the partition coefficient and solubility. An MDCKII-hMDR1 cell assay showed overall good permeability and no significant interaction with the P-glycoprotein transporter for all substrates except LSH002 and LSH031. The benzoxaboroles were degraded, to some extent, by skin enzymes but had stability superior to that of para-hydroxybenzoate compounds, which are known skin esterase substrates. Evaluation of permeation through reconstructed human epidermis showed LSH002 to be the most permeant, followed by LSH003 and LSH001. Skin disposition studies following finite drug formulation application to mouse skin demonstrated the highest permeation for LSH001, followed by LSH003 and LSH002, with a significantly larger amount of LSH001 than the other compounds being retained in skin. Finally, the efficacy of the leads (LSH001, LSH002, and LSH003) against Leishmania major was tested in vivo LSH001 suppressed lesion growth upon topical application, and LSH003 reduced the lesion size following oral administration.

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Several derivatives of aminobenzoboroxole have been prepared starting from 2-boronobenzaldehyde. All of these derivatives have been evaluated for their anti-mycobacterial activity on Mycobacterium smegmatis and cytotoxicity on breast cancer cell line MCF7. Based on these studies, all the tested molecules have been found to be generally non-toxic and benzoboroxoles with unsubstituted (primary) amines have been found to exhibit good anti-mycobacterial activity. Some of the key compounds have been evaluated for their anti-tubercular activity on Mycobacterium tuberculosis H37Rv using 7H9 and GAST media. 7-Bromo-6-aminobenzoboroxole 4 has been identified as the lead candidate compound for further development.

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5-Fluoro-2,1-benzoxaborol-1(3H)-ol, a potent antifungal drug also known as Tavaborole or AN2690, has been compared with its three isomers in terms of its activity against several fungi as well as pKa and multinuclear NMR characterization. The molecular and crystal structure of 6-fluoro-2,1-benzoxaborol-1(3H)-ol was determined and compared with that of AN2690.

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