5-(Sulfamoyl)thien-2-yl 1,3-oxazole inhibitors of carbonic anhydrase II with hydrophilic periphery

Hydrophilic derivatives of an earlier described series of carbonic anhydrase inhibitors have been designed, prepared and profiled against a panel of carbonic anhydrase isoforms, including the glaucoma-related hCA II. For all hydrophilic derivatives, computational prediction of intraocular permeability routes showed the predominance of conjunctival rather than corneal absorption. The potentially reactive primary or secondary amine periphery of these compounds makes them suitable candidates for bioconjugation to polymeric drug carriers. As was shown previously, the most active hCA II inhibitor is efficacious in alleviating intraocular pressure in normotensive rabbits with efficacy matching that of dorzolamide.Peer reviewe

Modeling experimental glaucoma for screening studies of antiglaucomatous activity

Introduction: In vivo screening studies, in which the efficacy of dozens of drugs is tested to select several applicants for further study of their safety in humans, are the main stage in the study of the pharmacodynamics of promising antiglaucoma drugs. This imposes a number of specific requirements both on experimental models of glaucoma and on laboratory animals used in the experiment. Materials and Methods: 32 male rabbits of the Soviet Сhinchilla breed, 6 male albino rabbits weighing 3-3.5 kg, and 20 outbred white rats weighing 220-250 g were used in total in experiments to reproduce the glaucoma process. All manipulations on the rabbit eye were performed by an ophthalmologist under general anesthesia with telazol. Triamcinolone (vitreous injection) was used to simulate glaucoma in rabbits, lauromacrogol 400 or fine kaolin (anterior chamber injection) was used to simulate glaucoma in rabbits; adrenaline hydrochloride (intraperitoneal administration) was used to simulate glaucoma in rats. Results and Discussion: Double intravitreal administration of a suspension of triamcinolone at a dose of 4 mg was the most attractive model in terms of the technique of reproducing the pathology and the results obtained in modeling glaucoma in rabbits. However, this model did not produce a stable increase in intraocular pressure (IOP). Doubling the dose of triamcinolone and replacing chinchilla rabbits with albinos did not lead to a positive result. The introduction of the venous sclerosing drug lauromacrogol 400 into the anterior chamber of the eye proved to be ineffective either. The introduction of finely dispersed kaolin into the anterior chamber of the eye of rabbits led to a persistent increase in IOP. The intraperitoneal administration of epinephrine hydrochloride to rats according to the described method gave no stable results. The increase in IOP became stable only after a significant increase in the dose of adrenaline. Conclusion: The conducted studies of four models of glaucoma and their three modifications in animals made it possible to select two of them, which contributed to a stable and fairly long-term increase in IOP in rabbits (introduction of finely dispersed kaolin into the anterior chamber of the eye) and rats (adrenaline-induced model)

Probing the 'bipolar' nature of the carbonic anhydrase active site: Aromatic sulfonamides containing 1,3-oxazol-5-yl moiety as picomolar inhibitors of cytosolic CA I and CA II isoforms

A series of potent inhibitors of human carbonic anhydrase (CA) isoforms I and II has been prepared via a direct, chemoselective sulfochlorination of a range of 1,3-oxazolyl benzenes and thiophenes, followed by primary sulfonamide synthesis. The latter functionality is a known zinc-binding group (ZBG) responsible for anchoring the inhibitors to the CA's zinc metal ion. The compound's periphery as well as the overall scaffold geometry was designed to enable optimal interactions with the two distinct sides of the enzyme's active site, one of which is lined with hydrophobic residues and while the other is predominantly hydrophilic. As a result, several compounds inhibiting the therapeutically important cytosolic CA I and CA II in picomolar range have been identified. These compounds are one of the most potent CA inhibitors identified to-date. Not only the remarkable (>10 000-fold), cytosolic CA I and CA II selectivity vs. the membrane-bound CA IX and CA XII isoforms, but also the pronounced CA II/I selectivity observed in some cases, allow considering this series as a set of isoform-selective chemical biology tools and promising starting points for drug candidate development

Primary mono- and bis-sulfonamides obtained via regiospecific sulfochlorination of N-arylpyrazoles: inhibition profile against a panel of human carbonic anhydrases

A diverse set of mono- and bis-sulfonamide was obtained via a direct, chemoselective sulfochlorination of readily available yet hitherto unexplored N-arylpyrazole template. Biochemical profiling of compounds thus obtained against a panel of human carbonic anhydrases (hCA I, hCA II, hCA IV and hCA VII) revealed a number of leads that are promising from the isoform selectivity prospective and exhibit potent inhibition profile (from nanomolar to micromolar range). The observed SAR trends have been rationalized by in silico docking of selected compounds into the active site of all four isoforms. The results reported in this paper clearly attest to the power of direct sulfochlorination as the means to create carbonic anhydrase focused sets in order to identify isoform selective inhibitors of closely related enzymes

A Series of Trifluoromethylisoxazolyl- and Trifluoromethylpyrazolyl- Substituted (Hetero)aromatic Sulfonamide Carbonic Anhydrase Inhibitors: Synthesis, and Convenient Prioritization Workflow for Further In Vivo Studies

Abstract: Aims: To synthesize novel sulfonamide inhibitors of carbonic anhydrase and develop in vitro prioritization workflow to select compounds for in vivo evaluation. Background: Carbonic anhydrase (CA) inhibitors gain significant attention in the context of drug discovery research for glaucoma, hypoxic malignancies, and bacterial infections. In previous works, we have successfully used direct sulfochlorination approach to develop diverse heterocyclic primary sulfonamides with remarkable activity and selectivity against therapeutically relevant CA isoforms. Objective: Synthesis and investigation of the CA inhibitory properties of novel trifluoromethylisoxa- zolyl- and trifluoromethylpyrazolyl-substituted (hetero)aromatic sulfonamides. Methods: Thirteen trifluoromethylisoxazolyl- and thirteen trifluoromethylpyrazolyl-substituted (het- ero)aromatic sulfonamides were synthesized by direct sulfochlorination of hydroxyisoxazolines and pyrazoles followed by reaction with ammonia. The compound structures were confirmed by 1H and 13 C NMR as well as element analysis. The obtained compounds were evaluated, using the CA es- terase activity assay, for their potential to block the catalytic activity of bovine CA (bCA). Results: Eight most potent compounds selected based on the esterase activity assay data were tested for direct affinity to the enzyme using the thermal shift assay (TSA). These compounds displayed Kd values (measured by TSA) in the double-digit nanomolar range, thus showing comparable activity to the reference drug acetazolamide

Human carbonic anhydrase inhibitory profile of mono- and bis-sulfonamides synthesized via a direct sulfochlorination of 3- and 4-(hetero)arylisoxazol-5-amine scaffolds

Three distinct series of isoxazole-based primary mono- and bis-sulfonamides have been synthesized via direct sulfochlorination, each of them delivering nanomolar inhibitors of human carbonic anhydrase. Certain pronounced SAR trends have been established and rationalized by in silico docking. These findings expand the structure-activity knowledge base for heterocycle-containing sulfonamide carbonic anhydrase inhibitors and further validate the power of direct electrophilic sulfochlorination as a means of introducing the pharmacophoric primary sulfonamide group into structurally diverse aromatic precursors

1,2,4-Oxadiazole/2-Imidazoline Hybrids: Multi-target-directed Compounds for the Treatment of Infectious Diseases and Cancer

Replacement of amide moiety with the 1,2,4-oxadiazole core in the scaffold of recently reported efflux pump inhibitors afforded a novel series of oxadiazole/2-imidazoline hybrids. The latter compounds exhibited promising antibacterial activity on both Gram-positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative (Escherichia coli, Pseudomonas fluorescens) strains. Furthermore, selected compounds markedly inhibited the growth of certain drug-resistant bacteria. Additionally, the study revealed the antiproliferative activity of several antibacterial frontrunners against pancreas ductal adenocarcinoma (PANC-1) cell line, as well as their type-selective monoamine oxidase (MAO) inhibitory profile

Monoamine oxidase inhibition properties of 2,1‑benzisoxazole derivatives

onoamine oxidase (MAO) are favoenzymes that metabolize neurotransmitter, dietary and xenobiotic amines to their corre sponding aldehydes with the production of hydrogen peroxide. Two isoforms, MAO-A and MAO-B, are expressed in humans and mammals, and display diferent substrate and inhibitor specifcities as well as diferent physiological roles. MAO inhibi tors are of much therapeutic value and are used for the treatment of neuropsychiatric and neurodegenerative disorders such as depression, anxiety disorders, and Parkinson’s disease. To discover MAO inhibitors with good potencies and interesting isoform specifcities, the present study synthesized a series of 2,1-benzisoxazole (anthranil) derivatives and evaluated them as in vitro inhibitors of human MAO. The compounds were in most instances specifc inhibitors of MAO-B with the most potent MAO-B inhibition observed for 7a (IC50=0.017 µM) and 7b (IC50=0.098 µM). The most potent MAO-A inhibition was observed for 3l (IC50=5.35 µM) and 5 (IC50=3.29 µM). It is interesting to note that 3-(2-aminoethoxy)-1,2-benzisoxazole derivatives, the 1,2-benzisoxazole, zonisamide, as well as the isoxazole compound, lefunomide, have been described as MAO inhibitors. This is however the frst report of MAO inhibition by derivatives of the 2,1-benzisoxazole structural isome

Copper-Catalyzed Selective Arylation of Oxadiazolones by Diaryliodonium Salts

The direct N-arylation of cyclic amides can be considered a pivotal issue for modern organic chemistry. Here, we report the method for copper-catalyzed N-arylation of diverse oxadiazolones by diaryliodonium salts in mild conditions in high yields (up to 92%) using available CuI as a catalyst. The developed method allows to efficiently utilize both symmetric and unsymmetric diaryliodonium salts bearing auxiliary groups such as 2,4,6-trimethoxyphenyl (TMP). The evaluation of steric effects in aryl moieties to the chemoselectivity of N- and O-arylation of the 1,2,4-oxadiazol-5(4H)-ones exhibited the high potential of mesityl-substituted diaryliodonium salts as a selective arylation reagent. The structural study suggests that steric accessibility of N-atom in 1,2,4-oxadiazol-5(4H)-ones impact to arylation with sterically hindered diaryliodonium salts. The synthetic application of proposed method was also demonstrated on selective arylation of 1,3,4-oxadiazol-2(3H)-ones and 1,2,4-oxadiazole-5-thiol