Synthesis, structure, properties and antimicrobial activity of para trifluoromethyl phenylboronic derivatives.

The [2-formyl-4-(trifluoromethyl)phenyl]boronic acid as well as its benzoxaborole and bis(benzoxaborole) derivatives were obtained and their properties studied. The 2-formyl compound displays an unusual structure in the crystalline state, with a significant twist of the boronic group, whereas in DMSO solution it tautomerizes with formation of a cyclic isomer. All the studied compounds exhibit relatively high acidity as well as a reasonable antimicrobial activity. Docking studies showed interactions of all the investigated compounds with the binding pocket of Candida albicans LeuRS. High activity against Bacillus cereus was determined for the 2-formyl compound as well as for the novel bis(benzoxaborole), whereas the studied benzoxaborole shows high antifungal action with MIC values equal to 7.8and 3.9 µg/mL against C. albicans and A. niger respectively. None of the studied compounds exhibits reasonable activity against E. coli.

Discovery of benzhydrol-oxaborole derivatives as Streptococcus pneumoniae leucyl-tRNA synthetase inhibitors.

Pneumonia caused by bacterium S. pneumoniae is a severe acute respiratory infectious disease with high morbidity and mortality, especially for children and immunity-compromised patients. The emergence of multidrug-resistant S. pneumoniae also presents a challenge to human health. Leucyl-tRNA synthetase (LeuRS) catalyzes the attachment of l-leucine to tRNALeu, which plays an essential role in protein translation and is considered an attractive antimicrobial drug target. In the present work, benzhydrol-oxaborole hybrid compounds were designed and synthesized as inhibitors of S. pneumoniae LeuRS. Exploration of the phenyl ring near Lysine 389 eventually yielded compounds 46 and 54 with submicromolar inhibitory potency. The co-crystal of compound 54 in the editing domain pocket of SpLeuRS was obtained and confirmed the formation of an additional hydrogen bond between the carbonyl of 54 and Lysine 389. It also showed anti-pneumococcal activity in vitro. The structure-activity relationship was discussed. This work will provide an essential foundation for the further development of anti-pneumococcal agents by targeting LeuRS.

In Vitro Susceptibility Testing of GSK656 against Mycobacterium Species.

In this study, we aimed to assess the in vitro susceptibility to GSK656 among multiple mycobacterial species and to investigate the correlation between leucyl-tRNA synthetase (LeuRS) sequence variations and in vitro susceptibility to GSK656 among mycobacterial species. A total of 187 mycobacterial isolates, comprising 105 Mycobacterium tuberculosis isolates and 82 nontuberculous mycobacteria (NTM) isolates, were randomly selected for the determination of in vitro susceptibility. For M. tuberculosis, 102 of 105 isolates had MICs of ≤0.5 mg/liter, demonstrating a MIC50 of 0.063 mg/liter and a MIC90 of 0.25 mg/liter. An epidemiological cutoff value of 0.5 mg/liter was proposed for identification of GSK656-resistant M. tuberculosis strains. For NTM, the MIC50 and MIC90 values were >8.0 mg/liter for both Mycobacterium intracellulare and Mycobacterium avium In contrast, all Mycobacterium abscessus isolates had MICs of ≤0.25 mg/liter, yielding a MIC90 of 0.063 mg/liter. LeuRS from M. abscessus showed greater sequence similarity to M. tuberculosis LeuRS than to LeuRSs from M. avium and M. intracellulare Sequence alignment revealed 28 residues differing between LeuRSs from M. avium and M. intracellulare and LeuRSs from M. tuberculosis and M. abscessus; among them, 15 residues were in the drug binding domain. Structure modeling revealed that several different residues were close to the tRNA-LeuRS interface or the entrance of the drug-tRNA binding pocket. In conclusion, our data demonstrate significant species diversity in in vitro susceptibility to GSK656 among various mycobacterial species. GSK656 has potent efficacy against M. tuberculosis and M. abscessus, whereas inherent resistance was noted for M. intracellulare and M. avium.

EXPANDING INFANT MENTAL HEALTH TREATMENT SERVICES TO AT-RISK PRESCHOOLERS AND THEIR FAMILIES THROUGH THE INTEGRATION OF RELATIONAL PLAY THERAPY.

The expansion of infant mental health (IMH) to at-risk preschoolers and their families has contributed to the integration of relational play therapy (RPT) into IMH treatment services for this population. Integrating RPT allows access to specialized play and expressive techniques specific to preschool and family development, which improves the clinical ability to meet the multiple and complex needs of at-risk parent-child dyads and their families. This article will examine the RPT literature and explore the similarities and differences between IMH and RPT. In addition, two case studies will highlight a five-phase, integrative clinical-treatment process and provide insight into how IMH clinicians are integrating RPT models and maintaining adherence to the IMH treatment approach.

Pass the boron: benzoxaboroles as antiparasite drugs.

The development of new drug modalities has been facilitated recently by the introduction of boron as a component of organic compounds, and specifically within a benzoxaborale scaffold. This has enabled exploration of new chemical space and the development of effective compounds targeting a broad range of morbidities, including infections by protozoa, fungi, worms, and bacteria. Most notable is the recent demonstration of a single oral dose cure using acoziborole against African trypanosomiasis. Common and species-/structure-specific interactions between benzoxaboroles and parasite species have emerged and provide vital insights into the mechanisms of cidality, as well as potential challenges in terms of resistance and/or side effects. Here, we discuss the literature specific to benzoxaborole studies in parasitic protists and consider unanswered questions concerning this important new drug class.

Design and synthesis of N-(3-sulfamoylphenyl)amides as Trypanosoma brucei leucyl-tRNA synthetase inhibitors.

The protozoan parasite Trypanosoma brucei (T. brucei) causes human African trypanosomiasis (HAT), which is a fatal and neglected disease in the tropic areas, and new treatments are urgently needed. Leucyl-tRNA synthetase (LeuRS) is an attractive target for the development of antimicrobial agents. In this work, starting from the hit compound thiourea ZCL539, we designed and synthesized a series of amides as effective T. brucei LeuRS (TbLeuRS) synthetic site inhibitors. The most potent compounds 74 and 91 showed IC50 of 0.24 and 0.25 µM, which were about 700-fold more potent than the starting hit compound. The structure-activity relationship was also discussed. These compounds provided a new scaffold and lead compounds for further development of antitrypanosomal agents.

Recent developments in the medicinal chemistry of single boron atom-containing compounds.

Various boron-containing drugs have been approved for clinical use over the past two decades, and more are currently in clinical trials. The increasing interest in boron-containing compounds is due to their unique binding properties to biological targets; for example, boron substitution can be used to modulate biological activity, pharmacokinetic properties, and drug resistance. In this perspective, we aim to comprehensively review the current status of boron compounds in drug discovery, focusing especially on progress from 2015 to December 2020. We classify these compounds into groups showing anticancer, antibacterial, antiviral, antiparasitic and other activities, and discuss the biological targets associated with each activity, as well as potential future developments.

Design and synthesis of α-phenoxy-N-sulfonylphenyl acetamides as Trypanosoma brucei Leucyl-tRNA synthetase inhibitors.

Human African trypanosomiasis (HAT), caused by the parasitic protozoa Trypanosoma brucei, is one of the fatal diseases in tropical areas and current medicines are insufficient. Thus, development of new drugs for HAT is urgently needed. Leucyl-tRNA synthetase (LeuRS), a recently clinically validated antimicrobial target, is an attractive target for development of antitrypanosomal drugs. In this work, we report a series of α-phenoxy-N-sulfonylphenyl acetamides as T. brucei LeuRS inhibitors. The most potent compound 28g showed an IC50 of 0.70 µM which was 250-fold more potent than the starting hit compound 1. The structure-activity relationship was also discussed. These acetamides provided a new scaffold and lead compounds for the further development of clinically useful antitrypanosomal agents.

Aminoacyl-tRNA synthetases in cell signaling.

Aminoacyl-tRNA synthetases (ARSs) are a family of essential "housekeeping" enzymes ubiquitous in the three major domains of life. ARSs uniquely connect the essential minimal units of both major oligomer classes-the 3-nucleotide codons of oligonucleotides and the amino acids of proteins. They catalyze the esterification of amino acids to the 3'-end of cognate transfer RNAs (tRNAs) bearing the correct anticodon triplet to ensure accurate transfer of information from mRNA to protein according to the genetic code. As an essential translation factor responsible for the first biochemical reaction in protein biosynthesis, ARSs control protein production by catalyzing aminoacylation, and by editing of mischarged aminoacyl-tRNAs to maintain translational fidelity. In addition to their primary enzymatic activities, many ARSs have noncanonical functions unrelated to their catalytic activity in protein synthesis. Among the ARSs with "moonlighting" activities, several, including GluProRS (or EPRS), LeuRS, LysRS, SerRS, TyrRS, and TrpRS, exhibit cell signaling-related activities that sense environmental signals, regulate gene expression, and modulate cellular functions. ARS signaling functions generally depend on catalytically-inactive, appended domains not present in ancient enzyme forms, and are activated by stimulus-dependent post-translational modification. Activation often results in cellular re-localization and gain of new interacting partners. The newly formed ARS-bearing complexes conduct a host of signal transduction functions, including immune response, mTORC1 pathway signaling, and fibrogenic and angiogenic signaling, among others. Because noncanonical functions of ARSs in signal transduction are uncoupled from canonical aminoacylation functions, function-specific inhibitors can be developed, thus providing promising opportunities and therapeutic targets for treatment of human disease.

Antibacterial Activity and Mode of Action of a Sulfonamide-Based Class of Oxaborole Leucyl-tRNA-Synthetase Inhibitors.

Benzoxaboroles are a class of boron-containing compounds with a broad range of biological activities. A subset of benzoxaboroles have antimicrobial activity due primarily to their ability to inhibit leucyl-tRNA synthetase (LeuRS) via the oxaborole tRNA-trapping mechanism, which involves the formation of a stable tRNALeu-benzoxaborole adduct in which the boron atom interacts with the 2'- and 3'-oxygen atoms of the terminal 3' tRNA adenosine. We sought to identify other antibacterial targets for this promising class of compounds by means of mode-of-action studies, and we selected a nitrophenyl sulfonamide based oxaborole (PT638) as a probe molecule because it had potent antibacterial activity (MIC of 0.4 µg/mL against methicillin-resistant Staphylococcus aureus) but did not inhibit LeuRS (IC50 > 100 µM). Analogues of PT638 were synthesized to explore the importance of the sulfonamide linker and the impact of altering the functionalization of the phenyl ring. These structure-activity-relationship studies revealed that the nitro substituent was essential for activity. To identify the target for PT638, we raised resistant strains of S. aureus, and whole-genome sequencing revealed mutations in leuRS, suggesting that the target for this compound was indeed LeuRS, despite the lack of enzyme inhibition. Subsequent analysis of PT638 metabolism demonstrated that bacterial nitroreductases readily converted this compound into the amino analogue, which inhibited LeuRS with an IC50 of 3.0 ± 1.2 µM, demonstrating that PT638 is thus a prodrug.

Structural simplification: an efficient strategy in lead optimization.

The trend toward designing large hydrophobic molecules for lead optimization is often associated with poor drug-likeness and high attrition rates in drug discovery and development. Structural simplification is a powerful strategy for improving the efficiency and success rate of drug design by avoiding "molecular obesity". The structural simplification of large or complex lead compounds by truncating unnecessary groups can not only improve their synthetic accessibility but also improve their pharmacokinetic profiles, reduce side effects and so on. This review will summarize the application of structural simplification in lead optimization. Numerous case studies, particularly those involving successful examples leading to marketed drugs or drug-like candidates, will be introduced and analyzed to illustrate the design strategies and guidelines for structural simplification.