ABSTRACT
Novel l-valinate amide benzoxaboroles and analogues were designed and synthesized for a structure-activity-relationship (SAR) investigation to optimize the growth inhibitory activity against Trypanosoma congolense (T. congolense) and Trypanosoma vivax (T. vivax) parasites. The study identified 4-fluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborole-6-carbonyl)-l-valinate (5, AN11736), which showed IC50 values of 0.15â¯nM against T. congolense and 1.3â¯nM against T. vivax, and demonstrated 100% efficacy with a single dose of 10â¯mg/kg against both T. congolense and T. vivax in mouse models of infection (IP dosing) and in the target animal, cattle, dosed intramuscularly. AN11736 has been advanced to early development studies.
Subject(s)
Antiprotozoal Agents/chemical synthesis , Boron Compounds/chemical synthesis , Trypanosomiasis, African/drug therapy , Valine/analogs & derivatives , Animals , Antiprotozoal Agents/pharmacology , Antiprotozoal Agents/therapeutic use , Boron Compounds/pharmacology , Boron Compounds/therapeutic use , Cattle , Mice , Structure-Activity Relationship , Trypanosoma congolense/drug effects , Trypanosoma vivax/drug effects , Trypanosomiasis, African/pathology , Trypanosomiasis, African/veterinary , Valine/chemical synthesis , Valine/pharmacology , Valine/therapeutic useABSTRACT
Psoriasis and atopic dermatitis are skin diseases affecting millions of patients. Here, we characterize benzoxaborole phosphodiesterase (PDE)-4 inhibitors, a new topical class that has demonstrated therapeutic benefit for psoriasis and atopic dermatitis in phase 2 or phase 3 studies. Crisaborole [AN2728, 4-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)benzonitrile], compd2 [2-ethoxy-6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)nicotinonitrile], compd3 [6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)-2-(2-isopropoxyethoxy)nicotinonitrile], and compd4 [5-chloro-6-((1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-5-yl)oxy)-2-((4-oxopentyl)oxy)nicotinonitrile] are potent PDE4 inhibitors with similar affinity for PDE4 isoforms and equivalent inhibition on the catalytic domain and the full-length enzyme. These benzoxaboroles are less active on other PDE isozymes. Compd4 binds to the catalytic domain of PDE4B2 with the oxaborole group chelating the catalytic bimetal and overlapping with the phosphate in cAMP during substrate hydrolysis, and the interaction extends into the adenine pocket. In cell culture, benzoxaborole PDE4 inhibitors suppress the release of tumor necrosis factor-α, interleukin (IL)-23, IL-17, interferon-γ, IL-4, IL-5, IL-13, and IL-22, and these cytokines contribute to the pathologic changes in skin structure and barrier functions as well as immune dysregulation in atopic dermatitis and psoriasis. Treatment with compd3 or N(6),2'-O-dibutyryladenosine 3',5'-cyclic monophosphate increases cAMP response element binding protein phosphorylation in human monocytes and decreases extracellular signal-regulated kinase phosphorylation in human T cells; these changes lead to reduced cytokine production and are among the mechanisms by which compd3 blocks cytokine release. Topical compd3 penetrates the skin and suppresses phorbol myristate acetate-induced IL-13, IL-22, IL-17F, and IL-23 transcription and calcipotriol-induced thymic stromal lymphopoietin expression in mouse skin. Skin thinning is a major dose-limiting side effect of glucocorticoids. By contrast, repeated application of compd3 did not thin mouse skin. These findings show the potential benefits and safety of benzoxaborole PDE4 inhibitors for the treatment of psoriasis and atopic dermatitis.
Subject(s)
Boron Compounds/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Dermatitis, Atopic/drug therapy , Phosphodiesterase 4 Inhibitors/pharmacology , Psoriasis/drug therapy , Skin/drug effects , Skin/pathology , Administration, Topical , Animals , Boron Compounds/administration & dosage , Boron Compounds/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Catalytic Domain , Cyclic AMP Response Element-Binding Protein/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 4/chemistry , Cytokines/metabolism , Dermatitis, Atopic/metabolism , Dermatitis, Atopic/pathology , Female , Gene Expression Regulation/drug effects , Leukocytes/drug effects , Leukocytes/metabolism , Mice , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Models, Molecular , Phosphodiesterase 4 Inhibitors/administration & dosage , Phosphodiesterase 4 Inhibitors/therapeutic use , Phosphorylation/drug effects , Psoriasis/metabolism , Psoriasis/pathology , Skin/metabolism , Thymic Stromal LymphopoietinABSTRACT
Novel isoxazoline amide benzoxaboroles were designed and synthesized to optimize the ectoparasiticide activity of this chemistry series against ticks and fleas. The study identified an orally bioavailable molecule, (S)-N-((1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-yl)methyl)-2-methyl-4-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzamide (23), with a favorable pharmacodynamics profile in dogs (Cmax=7.42ng/mL; Tmax=26.0h; terminal half-life t1/2=127h). Compound 23, a development candidate, demonstrated 100% therapeutic effectiveness within 24h of treatment, with residual efficacy of 97% against American dog ticks (Dermacentor variabilis) on day 30 and 98% against cat fleas (Ctenocephalides felis) on day 32 after a single oral dose at 25mg/kg in dogs.
Subject(s)
Amides/pharmacology , Antiparasitic Agents/pharmacology , Boron Compounds/pharmacology , Ctenocephalides/drug effects , Dermacentor/drug effects , Ectoparasitic Infestations/drug therapy , Isoxazoles/pharmacology , Administration, Oral , Amides/administration & dosage , Amides/chemistry , Animals , Antiparasitic Agents/administration & dosage , Antiparasitic Agents/chemistry , Boron Compounds/administration & dosage , Boron Compounds/chemistry , Cats , Dogs , Dose-Response Relationship, Drug , Ectoparasitic Infestations/parasitology , Isoxazoles/administration & dosage , Isoxazoles/chemistry , Molecular Structure , Parasitic Sensitivity Tests , Structure-Activity RelationshipABSTRACT
A novel series of isoxazoline benzoxaborole small molecules was designed and synthesized for a structure-activity relationship (SAR) investigation to assess the ectoparasiticide activity against ticks and fleas. The study identified an orally bioavailable molecule, (S)-3,3-dimethyl-5-(5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)benzo[c][1,2]oxaborol-1(3H)-ol (38, AN8030), which was long lasting in dogs (t1/2=22 days). Compound 38 demonstrated 97.6% therapeutic effectiveness within 24 h of treatment, with residual efficacy of 95.3% against American dog ticks (Dermacentor variabilis) on day 30% and 100% against cat fleas (Ctenocephalides felis) on day 32 after a single oral dose at 50 mg/kg in dogs.
Subject(s)
Boron Compounds/chemistry , Dog Diseases/drug therapy , Drug Discovery , Ectoparasitic Infestations/drug therapy , Isoxazoles/chemical synthesis , Administration, Oral , Animals , Boron Compounds/administration & dosage , Boron Compounds/pharmacology , Dog Diseases/parasitology , Dogs , Isoxazoles/administration & dosage , Isoxazoles/chemistry , Isoxazoles/pharmacology , Molecular Structure , Structure-Activity Relationship , Time FactorsABSTRACT
Gram-negative bacteria cause approximately 70% of the infections in intensive care units. A growing number of bacterial isolates responsible for these infections are resistant to currently available antibiotics and to many in development. Most agents under development are modifications of existing drug classes, which only partially overcome existing resistance mechanisms. Therefore, new classes of Gram-negative antibacterials with truly novel modes of action are needed to circumvent these existing resistance mechanisms. We have previously identified a new a way to inhibit an aminoacyl-tRNA synthetase, leucyl-tRNA synthetase (LeuRS), in fungi via the oxaborole tRNA trapping (OBORT) mechanism. Herein, we show how we have modified the OBORT mechanism using a structure-guided approach to develop a new boron-based antibiotic class, the aminomethylbenzoxaboroles, which inhibit bacterial leucyl-tRNA synthetase and have activity against Gram-negative bacteria by largely evading the main efflux mechanisms in Escherichia coli and Pseudomonas aeruginosa. The lead analogue, AN3365, is active against Gram-negative bacteria, including Enterobacteriaceae bearing NDM-1 and KPC carbapenemases, as well as P. aeruginosa. This novel boron-based antibacterial, AN3365, has good mouse pharmacokinetics and was efficacious against E. coli and P. aeruginosa in murine thigh infection models, which suggest that this novel class of antibacterials has the potential to address this unmet medical need.
Subject(s)
Amino Acyl-tRNA Synthetases/antagonists & inhibitors , Anti-Bacterial Agents/pharmacology , Boron Compounds/pharmacology , Escherichia coli/drug effects , Gram-Negative Bacterial Infections/drug therapy , Pseudomonas aeruginosa/drug effects , Amino Acyl-tRNA Synthetases/metabolism , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacokinetics , Bacterial Proteins/antagonists & inhibitors , Bacterial Proteins/metabolism , Boron Compounds/chemical synthesis , Boron Compounds/pharmacokinetics , Crystallography, X-Ray , Drug Discovery , Drug Resistance, Multiple, Bacterial/drug effects , Escherichia coli/enzymology , Female , Gram-Negative Bacterial Infections/microbiology , Humans , Leucine/metabolism , Mice , Microbial Sensitivity Tests , Molecular Docking Simulation , Pseudomonas aeruginosa/enzymology , Structure-Activity Relationship , Thigh/microbiology , beta-Lactamase Inhibitors , beta-Lactamases/metabolismABSTRACT
Benzoxaboroles are a novel class of drug-like compounds that have been rich sources of novel inhibitors for various enzymes and of new drugs. While examining benzoxaborole activity in phenotypic screens, our attention was attracted by the (aminomethylphenoxy)benzoxaborole family, which potently inhibited Toll-like receptor-stimulated cytokine secretion from leukocytes. After considering their structure-activity relationships and the central role of kinases in leukocyte biology, we performed a kinome-wide screen to investigate the members of the (aminomethylphenoxy)benzoxaborole family. This technique identified Rho-activated kinase (ROCK) as a target. We showed competitive behavior, with respect to ATP, and then determined the ROCK2-drug cocrystal structure. The drug occupies the ATP site in which the oxaborole moiety provides hydrogen bond donors and acceptors to the hinge, and the aminomethyl group interacts with the magnesium/ATP-interacting aspartic acid common to protein kinases. The series exhibits excellent selectivity against most of the kinome, with greater than 15-fold selectivity against the next best member of the AGC protein kinase subfamily. Medicinal chemistry efforts with structure-based design resulted in a compound with a Ki of 170 nM. Cellular studies revealed strong enzyme inhibition rank correlation with suppression of intracellular phosphorylation of a ROCK substrate. The biochemical potencies of these compounds also translated to functional activity, causing smooth muscle relaxation in rat aorta and guinea pig trachea. The series exhibited oral availability and one member reduced rat blood pressure, consistent with ROCK's role in smooth muscle contraction. Thus, the benzoxaborole moiety represents a novel hinge-binding kinase scaffold that may have potential for therapeutic use.
Subject(s)
Boron Compounds/metabolism , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , rho-Associated Kinases/antagonists & inhibitors , rho-Associated Kinases/metabolism , Animals , Aorta, Thoracic/drug effects , Blood Pressure/drug effects , Cytokines/blood , Humans , Jurkat Cells , Models, Molecular , Muscle Contraction/drug effects , Muscle Relaxation/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth, Vascular/drug effects , Myocytes, Smooth Muscle/drug effects , Phosphorylation , Protein Kinase Inhibitors/chemistry , Protein Phosphatase 1/metabolism , Rats , Rats, Inbred SHR , Rats, Sprague-Dawley , Structure-Activity Relationship , Trachea/drug effects , rho-Associated Kinases/geneticsABSTRACT
Pro-inflammatory cytokines play a critical role in the development of autoimmune and inflammatory diseases. Targeting the cytokine environment has proven efficient for averting inflammation. In this study, we reported that 6-[4-(aminomethyl)-2-chlorophenoxyl]benzo[c][1,2]oxaborol-1(3H)-ol (AN3485), a benzoxaborole analog, inhibited TLR2-, TLR3-, TLR4-, and TLR5-mediated TNF-α, IL-1ß, and IL-6 release from human PBMCs and isolated monocytes with IC(50) values ranging from 18 to 580 nM, and the inhibition was mediated at the transcriptional level. Topical administration of AN3485 significantly reduced PMA-induced contact dermatitis and oxazolone-induced delayed-type hypersensitivity in mice, indicating its capability of penetrating skin and potential topical application in skin inflammation. Oral administration of AN3485 showed dose-dependent suppression of LPS-induced TNF-α and IL-6 production in mice with an ED(90) of 30 mg/kg. Oral AN3485, 35 mg/kg, twice a day, suppressed collagen-induced arthritis in mice over a 20-day period. The potent anti-inflammatory activity in in vitro and in vivo disease models makes AN3485 an attractive therapeutic lead for a variety of cutaneous and systemic inflammatory diseases.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Arthritis/drug therapy , Boron Compounds/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Dermatitis, Allergic Contact/drug therapy , Drug Hypersensitivity/drug therapy , Hypersensitivity, Delayed/drug therapy , Toll-Like Receptors/antagonists & inhibitors , Administration, Oral , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Anti-Inflammatory Agents, Non-Steroidal/pharmacokinetics , Anti-Inflammatory Agents, Non-Steroidal/toxicity , Arthritis/immunology , Arthritis/metabolism , Boron Compounds/administration & dosage , Boron Compounds/pharmacokinetics , Boron Compounds/toxicity , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/toxicity , Cell Survival/drug effects , Cells, Cultured , Cytokines/biosynthesis , Cytokines/metabolism , Dermatitis, Allergic Contact/etiology , Dermatitis, Allergic Contact/immunology , Dermatitis, Allergic Contact/metabolism , Dose-Response Relationship, Drug , Drug Hypersensitivity/etiology , Drug Hypersensitivity/immunology , Drug Hypersensitivity/metabolism , Female , Humans , Hypersensitivity, Delayed/chemically induced , Hypersensitivity, Delayed/immunology , Hypersensitivity, Delayed/metabolism , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Lipopolysaccharides/pharmacology , Male , Mice , Mice, Inbred BALB CABSTRACT
A series of novel 6-(aminomethylphenoxy)benzoxaborole analogs was synthesized for the investigation of the structure-activity relationship of the inhibition of TNF-alpha, IL-1beta, and IL-6, from lipopolysaccharide stimulated peripheral blood mononuclear cells. Compounds 9d and 9e showed potent activity against all three cytokines with IC50 values between 33 and 83nM. Chloro substituted analog 9e (AN3485) is considered to be a promising lead for novel anti-inflammatory agent with a favorable pharmacokinetic profile.
Subject(s)
Anti-Inflammatory Agents/chemistry , Benzoxazoles/chemistry , Boron Compounds/chemistry , Bridged Bicyclo Compounds, Heterocyclic/metabolism , Animals , Anti-Inflammatory Agents/metabolism , Anti-Inflammatory Agents/pharmacokinetics , Boron Compounds/metabolism , Boron Compounds/pharmacokinetics , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Half-Life , Humans , Interleukin-1beta/antagonists & inhibitors , Interleukin-1beta/metabolism , Interleukin-6/antagonists & inhibitors , Interleukin-6/metabolism , Kinetics , Leukocytes, Mononuclear/drug effects , Lipopolysaccharides/toxicity , Mice , Protein Binding , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Structure-activity relationships of 6-(benzoylamino)benzoxaborole analogs were investigated for the inhibition of TNF-α, IL-1ß, and IL-6 from lipopolysaccharide stimulated peripheral blood mononuclear cells. Compound 1q showed potent activity against all three cytokines with IC50 values between 0.19 and 0.50µM, inhibited LPS-induced TNF-α and IL-6 elevation in mice and improved collagen-induced arthritis in mice. Compound 1q (AN4161) is considered to be a promising lead for novel anti-inflammatory agent with an excellent pharmacokinetic profile.
Subject(s)
Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Arthritis, Experimental/drug therapy , Benzene Derivatives/chemistry , Benzene Derivatives/therapeutic use , Boron Compounds/chemistry , Boron Compounds/therapeutic use , Animals , Anti-Inflammatory Agents/pharmacokinetics , Anti-Inflammatory Agents/pharmacology , Benzene Derivatives/pharmacokinetics , Benzene Derivatives/pharmacology , Boron Compounds/pharmacokinetics , Boron Compounds/pharmacology , Interleukin-1beta/immunology , Interleukin-6/immunology , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Lipopolysaccharides/immunology , Mice , Structure-Activity Relationship , Tumor Necrosis Factor-alpha/immunologyABSTRACT
Trypanosoma cruzi, the agent of Chagas disease, probably infects tens of millions of people, primarily in Latin America, causing morbidity and mortality. The options for treatment and prevention of Chagas disease are limited and underutilized. Here we describe the discovery of a series of benzoxaborole compounds with nanomolar activity against extra- and intracellular stages of T. cruzi. Leveraging both ongoing drug discovery efforts in related kinetoplastids, and the exceptional models for rapid drug screening and optimization in T. cruzi, we have identified the prodrug AN15368 that is activated by parasite carboxypeptidases to yield a compound that targets the messenger RNA processing pathway in T. cruzi. AN15368 was found to be active in vitro and in vivo against a range of genetically distinct T. cruzi lineages and was uniformly curative in non-human primates (NHPs) with long-term naturally acquired infections. Treatment in NHPs also revealed no detectable acute toxicity or long-term health or reproductive impact. Thus, AN15368 is an extensively validated and apparently safe, clinically ready candidate with promising potential for prevention and treatment of Chagas disease.
Subject(s)
Chagas Disease , Prodrugs , Trypanocidal Agents , Trypanosoma cruzi , Animals , Chagas Disease/drug therapy , Chagas Disease/parasitology , Primates , Prodrugs/pharmacology , Prodrugs/therapeutic use , Trypanocidal Agents/pharmacology , Trypanocidal Agents/therapeutic useABSTRACT
PDE4 inhibitors are a validated approach as anti-inflammatory agents but are limited by systemic side effects including emesis. We report a soft-drug strategy incorporating a carboxylic ester group into boron-containing PDE4 inhibitors leading to the discovery of a series of benzoxaborole compounds with good potency (for example IC(50)=47 nM of compound 2) and low emetic activity. These compounds are intended for dermatological use further limiting possible systemic side effects.
Subject(s)
Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Boron/chemistry , Boron/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 4/metabolism , Phosphodiesterase 4 Inhibitors , Animals , Anti-Inflammatory Agents/blood , Anti-Inflammatory Agents/therapeutic use , Boron/blood , Boron/therapeutic use , Ear/pathology , Edema/drug therapy , Humans , MiceABSTRACT
The optimization of a series of benzimidazole-benzoxaborole hybrid molecules linked via a ketone that exhibit good activity against Onchocerca volvulus, a filarial nematode responsible for the disease onchocerciasis, also known as river blindness, is described. The lead identified in this series, 21 (AN15470), was found to have acceptable pharmacokinetic properties to enable an evaluation following oral dosing in an animal model of onchocerciasis. Compound 21was effective in killing worms implanted in Mongolian gerbils when dosed orally as a suspension at 100 mg/kg/day for 14 days but not when dosed orally at 100 mg/kg/day for 7 days.
Subject(s)
Benzimidazoles/therapeutic use , Boron Compounds/therapeutic use , Ketones/chemistry , Onchocerciasis, Ocular/drug therapy , Administration, Oral , Animals , Benzimidazoles/pharmacokinetics , Boron Compounds/pharmacokinetics , Disease Models, Animal , Female , Filaricides/pharmacokinetics , Filaricides/therapeutic use , Gerbillinae , MaleABSTRACT
A series of benzimidazole-benzoxaborole hybrid molecules linked via an amide linker are described that exhibit good in vitro activity against Onchocerca volvulus, a filarial nematode responsible for the disease onchocerciasis, also known as river blindness. The lead identified in this series, 8a (AN8799), was found to have acceptable pharmacokinetic properties to enable evaluation in animal models of human filariasis. Compound 8a was effective in killing Brugia malayi, B. pahangi, and Litomosoides sigmodontis worms present in Mongolian gerbils when dosed subcutaneously as a suspension at 100 mg/kg/day for 14 days but not when dosed orally at 100 mg/kg/day for 28 days. The measurement of plasma levels of 8a at the end of the dosing period and at the time of sacrifice revealed an interesting dependence of activity on the extended exposure for both 8a and the positive control, flubendazole.
Subject(s)
Benzimidazoles/therapeutic use , Boron Compounds/therapeutic use , Brugia/drug effects , Onchocerciasis/drug therapy , Amides , Animals , Benzimidazoles/pharmacokinetics , Boron Compounds/pharmacokinetics , Female , Filaricides/pharmacokinetics , Filaricides/therapeutic use , Gerbillinae , Male , Onchocerca volvulus/drug effectsABSTRACT
A series of phenoxy benzoxaboroles were synthesized and screened for their inhibitory activity against PDE4 and cytokine release. 5-(4-Cyanophenoxy)-2,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2728) showed potent activity both in vitro and in vivo. This compound is now in clinical development for the topical treatment of psoriasis and being pursued for the topical treatment of atopic dermatitis.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Boron Compounds/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Dermatitis, Atopic/drug therapy , Dermatologic Agents/chemistry , Psoriasis/drug therapy , Administration, Topical , Animals , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Boron Compounds/administration & dosage , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Dermatitis, Atopic/pathology , Dermatologic Agents/administration & dosage , Edema/drug therapy , Edema/pathology , Humans , Mice , Psoriasis/pathology , Structure-Activity Relationship , U937 CellsABSTRACT
Onychomycosis is a challenging fungal infection to treat topically, likely due to the unique properties of the nail plate. This seemingly impenetrable barrier has high resistance to the passage of antifungal drugs in sufficient concentrations to kill the causative fungi deep in the nail bed. Recently, a new class of antifungal agent was described, termed oxaboroles, which have broad-spectrum activity. These oxaboroles were designed with properties believed to be required to allow for easier transit through the nail plate. Herein, we report (i) the nail penetration results of four oxaboroles that led to the selection of AN2690, (ii) the results of the nail penetration of AN2690 from four vehicles, and (iii) the nail penetration of AN2690 in its chosen vehicle compared to a commercial control, ciclopirox. AN2690 has superior penetration compared to ciclopirox, and achieves levels within and under the nail plate that suggest it has the potential to be an effective topical treatment for onychomycosis.
Subject(s)
Antifungal Agents/metabolism , Boron Compounds/metabolism , Bridged Bicyclo Compounds, Heterocyclic/metabolism , Nails/metabolism , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Boron Compounds/chemistry , Boron Compounds/pharmacology , Boron Compounds/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/therapeutic use , Chemistry, Pharmaceutical , Ciclopirox , Diffusion , Diffusion Chambers, Culture , Drug Compounding , Ethanol/chemistry , Hand Dermatoses/drug therapy , Humans , Molecular Structure , Onychomycosis/drug therapy , Permeability , Pharmaceutical Vehicles/chemistry , Pilot Projects , Propylene Glycol/chemistry , Pyridones/metabolism , Solubility , Time FactorsABSTRACT
A structure-activity relationship investigation for a more efficacious therapy to treat onychomycosis, a fungal infection of the toe and fingernails, led to the discovery of a boron-containing small molecule, 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690), which is currently in clinical trials for onychomycosis topical treatment.
Subject(s)
Antifungal Agents/chemical synthesis , Boron Compounds/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Onychomycosis/drug therapy , Administration, Topical , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Aspergillus fumigatus/drug effects , Boron Compounds/chemistry , Boron Compounds/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Candida/drug effects , Microbial Sensitivity Tests , Structure-Activity Relationship , Trichophyton/drug effectsABSTRACT
As bacteria continue to develop resistance toward current antibiotics, we find ourselves in a continual battle to identify new antibacterial agents and targets. We report herein a class of boron-containing compounds termed borinic esters that have broad spectrum antibacterial activity with minimum inhibitory concentrations (MIC) in the low microgram/mL range. These compounds were identified by screening for inhibitors against Caulobacter crescentus CcrM, an essential DNA methyltransferase from gram negative alpha-proteobacteria. In addition, we demonstrate that borinic esters inhibit menaquinone methyltransferase in gram positive bacteria using a new biochemical assay for MenH from Bacillus subtilis. Our data demonstrate the potential for further development of borinic esters as antibacterial agents as well as leads to explore more specific inhibitors against two essential bacterial enzymes.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Borinic Acids/chemical synthesis , DNA Modification Methylases/antagonists & inhibitors , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Bacillus subtilis/drug effects , Bacillus subtilis/enzymology , Borinic Acids/chemistry , Borinic Acids/pharmacology , Caulobacter crescentus/drug effects , Caulobacter crescentus/enzymology , DNA Modification Methylases/chemistry , Esters/chemical synthesis , Esters/chemistry , Esters/pharmacology , Gram-Negative Bacteria/enzymology , Gram-Negative Bacteria/growth & development , Gram-Positive Bacteria/enzymology , Gram-Positive Bacteria/growth & development , Kinetics , Microbial Sensitivity Tests , Proteobacteria/enzymology , Structure-Activity RelationshipABSTRACT
[structure: see text] UCS1025A and B, novel pentacyclic polyketides with an unprecedented furopyrrolizidine skeleton, were isolated from the fungus Acremonium sp. KY4917. The structures and stereochemistry were elucidated by a combination of two-dimensional NMR and X-ray crystallographic analysis. UCS1025A showed unique chemical equilibria involving three tautomeric isomers and exhibited antimicrobial activity and antiproliferative activity against human tumor cell lines.
Subject(s)
Acremonium/chemistry , Antineoplastic Agents/isolation & purification , Antineoplastic Agents/pharmacology , Pyrrolizidine Alkaloids/isolation & purification , Pyrrolizidine Alkaloids/pharmacology , Antineoplastic Agents/chemistry , Cell Line , Crystallography, X-Ray , Humans , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , Pyrrolizidine Alkaloids/chemistryABSTRACT
There is an increasing interest in in vivo metabolite identification in early drug discovery in order to (i) give a more complete picture of metabolic profile in investigational animal models, (ii) propose phase I and phase II metabolites using the same pharmacokinetic/toxicokinetic study samples, (iii) expose metabolically labile groups where chemical modifications could improve stability, and (iv) enable early safety assessment of metabolites. In the early discovery stage of our anti-inflammatory program, one novel benzoxaborole, AN6414, exhibiting both PDE4 enzyme and TNFα inhibition activities, became our primary candidate for further investigation. The traditional metabolite identifications usually require high dosed samples with long data scans and analysis. In this study, we conducted quick and more selective core-structure related precursor scans followed by daughter ion scans and identified a total of 10 major phase I and phase II metabolites using rat plasma samples from a toxicokinetic study at an oral dosing of 30 mg/kg. Plasma samples were treated with solid phase extraction (SPE) prior to LC/MS/MS. An AB SCIEX API 4000 QTRAP mass spectrometer coupled with a Shimadzu LC system was used for LC/MS/MS analysis. We found the major metabolites of AN6414 to be oxidative deboronation, protodeboronation, oxidation products and their sulfate-conjugated species. This analysis drove analoging efforts which improved the pharmacokinetic profile, namely, lowering clearance and increasing exposure relative to AN6414. Toxicity predictions by the software program DEREK suggest the identified potential metabolites to be safe.
Subject(s)
Anti-Inflammatory Agents/pharmacokinetics , Boron Compounds/pharmacokinetics , Chromatography, Liquid , Drug Discovery/methods , Phosphodiesterase 4 Inhibitors/pharmacology , Pyridines/pharmacokinetics , Tandem Mass Spectrometry , Administration, Oral , Animals , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/blood , Anti-Inflammatory Agents/urine , Area Under Curve , Biotransformation , Boron Compounds/administration & dosage , Boron Compounds/blood , Boron Compounds/toxicity , Female , Male , Metabolic Clearance Rate , Models, Biological , Oxidation-Reduction , Phosphodiesterase 4 Inhibitors/administration & dosage , Phosphodiesterase 4 Inhibitors/blood , Phosphodiesterase 4 Inhibitors/toxicity , Pyridines/administration & dosage , Pyridines/blood , Pyridines/toxicity , Rats , Rats, Sprague-Dawley , Risk Assessment , Software , Solid Phase Extraction , Sulfates/pharmacokineticsABSTRACT
We have used boron-based molecules to create novel, competitive, reversible inhibitors of phosphodiesterase 4 (PDE4). The co-crystal structure reveals a binding configuration which is unique compared to classical catechol PDE4 inhibitors, with boron binding to the activated water in the bimetal center. These phenoxybenzoxaboroles can be optimized to generate submicromolar potency enzyme inhibitors, which inhibit TNF-α, IL-2, IFN-γ, IL-5 and IL-10 activities in vitro and show safety and efficacy for topical treatment of human psoriasis. They provide a valuable new route for creating novel potent anti-PDE4 inhibitors.