Synthesis and in†vitro Anti-Inflammatory Activity of Novel Dendrobine Amide/Sulfonamide Derivatives.

A traditional Chinese medicine ingredient, dendrobine, has been demonstrated to have anti-inflammatory properties. However, due to its poor anti-inflammatory properties, its clinical use is limited. Consequently, we have designed and synthesized 32 new amide/sulfonamide dendrobine derivatives and screened their anti-inflammatory activities in vitro. Experiments showed that nitric oxide (NO) generation in lipopolysaccharide (LPS)-induced RAW264.7 cells was strongly reduced by derivative 14, with an IC50 of 2.96 µM. Western blot research revealed that 14 decreased the concentration-dependent expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (INOS). Molecular docking was used to predict the binding of the inflammation-associated proteins COX-2 and INOS to compound 14.

Synthesis, characterization of novel N-(4-cyano-1,3-oxazol-5-yl)sulfonamide derivatives and in†vitro screening their activity against NCI-60 cancer cell lines.

A novel series of N-(4-cyano-1,3-oxazol-5-yl)sulfonamides have been synthesized and characterized by IR, 1 H NMR, 13 C NMR spectroscopy, elemental analysis and chromato-mass-spectrometry. The anticancer activities of all newly synthesized compounds were evaluated via a single high-dose assay (10 µM) against 60 cancer cell lines by the National Cancer Institute (USA) according to its screening protocol. Among them, compounds 2 and 10 exhibited the highest activity against the 60 cancer cell lines panel in the one-dose assay. Compounds 2 and 10 showed inhibitory activity within the GI50 parameter and in five dose analyses. However, their cytostatic activity was only observed against some cancer cell lines, and cytotoxic concentration was outside the maximum used, i. e., >100 µM. The COMPARE analysis showed that the average graphs of the tested compounds have a moderate positive correlation with compounds with the L-cysteine analog and vinblastine (GI50 ) as well as paclitaxel (TGI), which target microtubules. Therefore, disruption of microtubule formation may be one of the mechanisms of the anticancer activity of the tested compounds, especially since among tubulin inhibitors with antitumor activity, compounds with an oxazole motif are widely represented. Therefore, N-(4-cyano-1,3-oxazol-5-yl)sulfonamides may be promising for further functionalization to obtain more active compounds.

Novel sulfonamide-phosphonate conjugates as carbonic anhydrase isozymes inhibitors.

The three-components one-pot Kabachnik-Fields reaction of sulfapyridine, diethyl phosphite, and aldehyde under thermal catalysis reaction condition in the presence of bismuth (III) triflate as a catalyst afford the corresponding sulfonamide-phosphonates (3a-3p) in good to excellent yields (78%-91%). The structures of the new synthesized compounds were elucidated and confirmed by variable spectroscopic studies. Single crystal X-ray studies for 3a, 3d, and 3i verified the proposed structure. The newly developed sulfonamide-phosphonates were evaluated for their inhibitory properties against four isoforms of human carbonic anhydrase (hCA I, II, IX, and XII). The results demonstrated that they exhibited greater potency in inhibiting hCA XII compared to hCA I, II, and IX, with Ki ranging from 5.1 to 51.1 nM. Compounds 3l and 3p displayed the highest potency, exhibiting selectivity ratios of I/XII >298.7 and 8.5, and II/XII ratios of 678.1 and 142.1, respectively. Molecular docking studies were conducted to explore their binding patterns within the binding pocket of CA XII. The results revealed that the sulfonamide NH group coordinated with the Zn2+ ion, and hydrogen bond interactions were observed with residue Thr200. Additionally, hydrophobic interactions were identified between the benzenesulfonamide phenyl ring and Leu198. Compounds 3p and 3l exhibited an additional hydrogen bonding interaction with other amino acid residues. These supplementary interactions may contribute to the enhanced potency and selectivity of these compounds toward the CA XII isoform.

Eco-friendly methods of synthesis and preliminary biological evaluation of sulfonamide derivatives of cyclic arylguanidines.

The chemotype of arylsulfonamide derivatives of cyclic arylguanidines is a source of molecules with valuable biological activities, including antimicrobial and antitumor properties. The methods of the synthesis presented in the literature are characterized with low selectivity and high environmental nuisance. In this publication, we present a developed alternative and earlier undescribed pathway C, for the synthesis of arylsulfonamide derivatives of cyclic arylguanidines (N-(1H-arylimidazol-2-yl)arylsulfonamides and N-(1,4-dihydroquinazolin-2-yl)arylsulfonamides), including reaction between 2-(methylsulfanyl)-benzimidazole or 2-(methylsulfanyl)-3,4-dihydroquinazoline with arylsulfonamides. We also optimized previously reported methods; A (reaction of 2-aminobenzimidazole or 2-amino-3,4-dihydroquinazoline with arylsulfonyl chlorides) and B (reaction of dimethyl-(arylsulfonyl)carbonodithioimidate with aryldiamines). The conducted research allowed achieving two independent ecological and quick methods of obtaining the desired products. We used ecological methods of ultrasound-assisted or microwave synthesis, solvent-free reactions and a"green" reaction environment. In both pathways, it has proven advantageous to use H2O as the solvent and K2CO3 (1 or 3 equivalent) as the basic agent. In the sonochemical variant, the efficiency reached B: 37-89 %, C: 90 % in 60 min (P = 80 W and f = 40 kHz), while in the microwave synthesis it was B: 38-74 %, C: 63-85 % in 0.5-4 min (P = 50 W). Path A led to a complementary substitution product (i.e. 1-(arylsulfonyl)-1H-benzimidazol-2-amine or 1-(arylsulfonyl)-1,4-dihydroquinazolin-2-amine). We obtained a small group of compounds that were tested for cytotoxicity. The 10f (N-(1,4-dihydroquinazolin-2-yl)naphthalene-1-sulfonamide) showed cytotoxic activity towards human astrocytoma cell line 1321 N1. The calculated IC50 value was 8.22 µM at 24 h timepoint (doxorubicin suppressed 1321 N1 cell viability with IC50 of 1.1 µM). The viability of the cells exposed to 10f for 24 h dropped to 48.0 % compared to vehicle control, while the cells treated with doxorubicin experienced decline to 47.5 %. We assessed its potential usefulness in pharmacotherapy in the ADMET study, confirming its ability to cross the blood-brain barrier (Pe = 5.0 ± 1.5 × 10-6 cm/s) and the safety of its potential use in terms of DDI and hepatotoxicity.

Degradation of sulfonamides in aquaculture wastewater by laccase-syringaldehyde mediator system: Response surface optimization, degradation kinetics, and degradation pathway.

As a new type of environmental pollutant, environmental antibiotic residues have attracted widespread attention, and the degradation and removal of antibiotics has become an engaging topic for scholars. In this paper, Novozym 51003 industrialized laccase and syringaldehyde were combined to degrade sulfonamides in aquaculture wastewater. Design Expert10 software was used for multiple regression analysis, and a response surface regression model was established to obtain the optimal degradation parameters. In the actual application, the degradation system could maintain a stable performance within 9 h, and timely supplement of the mediator could achieve a better continuous degradation effect. Low concentrations of heavy metals and organic matter would not significantly affect the degradation performance of the laccase-mediator system, making the degradation system suitable for a wide range of water quality. Enzymatic reaction kinetics demonstrated a strong affinity of sulfadiazine to the substrate. Ten degradation products were speculated using high-resolution mass spectrum based on the mass/charge ratios and the publication results. Four types of possible degradation pathways of sulfadiazine were deduced. This work provides a practical method for the degradation and removal of sulfonamide antibiotics in actual sewage.

Synthesis and Evaluation of Antioxidant, Anti-Edematogenic and Antinociceptive Properties of Selenium-Sulfa Compounds.

Herein we describe results for the synthesis and synthetic application of 4-amino-3-(arylselenyl)benzenesulfonamides, and preliminary evaluation of antioxidant, anti-edematogenic and antinociceptive properties. This class of compounds was synthesized in good yields by a reaction of commercially available sulfanilamide and diorganyl diselenides in the presence of 10 mol% of I2 . Furthermore, the synthesized compound 4-amino-3-(phenylselenyl)benzenesulfonamide (3 a) was evaluated on complete Freund's adjuvant (CFA)-induced acute inflammatory pain. Dose- and time-response curves of antinociceptive effect of compound 3 a were performed using this experimental model. Also, the effect of compound 3 a was monitored in a hot-plate test to evaluate the acute non-inflammatory antinociception. The open-field test was performed to evaluate the locomotor and exploratory behaviors of mice. Oxidative stress markers, such as glutathione peroxidase activity; reactive species, non-protein thiols, and lipid peroxidation levels were performed to investigate the antioxidant action of compound 3 a. Our findings suggest that the antioxidant effect of compound 3 a may contribute to reducing the nociception and suppress the signaling pathways of inflammation on the local injury induced by CFA. Thus, compound 3 a reduced the paw edema as well as the hyperalgesic behavior in mice, being a promising therapeutic agent for the treatment of painful conditions.

Tetrahydroquinazole-based secondary sulphonamides as carbonic anhydrase inhibitors: synthesis, biological evaluation against isoforms I, II, IV, and IX, and computational studies.

A library of variously decorated N-phenyl secondary sulphonamides featuring the bicyclic tetrahydroquinazole scaffold was synthesised and biologically evaluated for their inhibitory activity against human carbonic anhydrase (hCA) I, II, IV, and IX. Of note, several compounds were identified showing submicromolar potency and excellent selectivity for the tumour-related hCA IX isoform. Structure-activity relationship data attained for various substitutions were rationalised by molecular modelling studies in terms of both inhibitory activity and selectivity.

Complexation of uranyl (UO2)2+ with bidentate ligands: XRD, spectroscopic, computational, and biological studies.

Three new uranyl complexes [(UO2)(OAc)2(CMZ)], [(UO2)(OAc)2(MP)] and [(UO2)(OAc)2(SCZ)] were synthesized and characterized by elemental analysis, FT-IR, UV-Vis spectroscopy, powder XRD analysis, and molar conductivity. The IR analysis confirmed binding to the metal ion by the sulfur and ethoxy oxygen atoms in the carbimazole (CMZ) ligand, while in the 6-mercaptopurine (MP) ligand, the sulfur and the N7 nitrogen atom of a purine coordinated binding to the metal ion. The third ligand showed a 1:1 molar ratio and bound via sulfonamide oxygen and the nitrogen of the pyrimidine ring. Analysis of the synthesized complexes also showed that acetate groups had monodentate binding to the (UO22+). Density Functional Theory (DFT) calculations at the B3LYP level showed similar structures to the experimental results. Theoretical quantum parameters predicted the reactivity of the complexes in the order, [(UO2)(OAc)2(SCZ)] > [(UO2)(OAc)2(MP)]> [(UO2)(OAc)2(CMZ)]. DNA binding studies revealed that [(UO2)(OAc)2(SCZ)] and [(UO2)(OAc)2(CMZ)] have the highest binding constant (Kb) among the uranyl complexes. Additionally, strong binding of the MP and CMZ metal complexes to human serum albumin (HSA) were observed by both absorbance and fluorescence approaches. The antibacterial activity of the complexes was also evaluated against four bacterial strains: two gram-negative; Escherichia coli and Klebsiella pneumonia, and two gram-positive; Staphylococcus aureus and Streptococcus mutans. [(UO2)(OAc)2(MP)] had the greatest antibacterial activity against Klebsiella pneumonia, the gram-positive bacteria, with even higher activity than the standard antibiotic. In vitro cytotoxicity tests were also performed against three human cancer lines, and revealed the most cytotoxic complexes to be [(UO2)(OAc)2(SCZ)], which showed moderate activity against a colon cancer cell line. Thus, uranyl addition enhances the antibacterial and anticancer properties of the free ligands.

Discovery of New Imidazo[2,1-b]thiazole Derivatives as Potent Pan-RAF Inhibitors with Promising In Vitro and In Vivo Anti-melanoma Activity.

BRAF is an important component of MAPK cascade. Mutation of BRAF, in particular V600E, leads to hyperactivation of the MAPK pathway and uncontrolled cellular growth. Resistance to selective inhibitors of mutated BRAF is a major obstacle against treatment of many cancer types. In this work, a series of new (imidazo[2,1-b]thiazol-5-yl)pyrimidine derivatives possessing a terminal sulfonamide moiety were synthesized. Pan-RAF inhibitory effect of the new series was investigated, and structure-activity relationship is discussed. Antiproliferative activity of the target compounds was tested against the NCI-60 cell line panel. The most active compounds were further tested to obtain their IC50 values against cancer cells. Compound 27c with terminal open chain sulfonamide and 38a with a cyclic sulfamide moiety showed the highest activity in enzymatic and cellular assay, and both compounds were able to inhibit phosphorylation of MEK and ERK. Compound 38a was selected for testing its in vivo activity against melanoma. Cellular and animal activities are reported.

Prioritizing antiviral drugs against SARS-CoV-2 by integrating viral complete genome sequences and drug chemical structures.

The outbreak of a novel febrile respiratory disease called COVID-19, caused by a newfound coronavirus SARS-CoV-2, has brought a worldwide attention. Prioritizing approved drugs is critical for quick clinical trials against COVID-19. In this study, we first manually curated three Virus-Drug Association (VDA) datasets. By incorporating VDAs with the similarity between drugs and that between viruses, we constructed a heterogeneous Virus-Drug network. A novel Random Walk with Restart method (VDA-RWR) was then developed to identify possible VDAs related to SARS-CoV-2. We compared VDA-RWR with three state-of-the-art association prediction models based on fivefold cross-validations (CVs) on viruses, drugs and virus-drug associations on three datasets. VDA-RWR obtained the best AUCs for the three fivefold CVs, significantly outperforming other methods. We found two small molecules coming together on the three datasets, that is, remdesivir and ribavirin. These two chemical agents have higher molecular binding energies of - 7.0 kcal/mol and - 6.59 kcal/mol with the domain bound structure of the human receptor angiotensin converting enzyme 2 (ACE2) and the SARS-CoV-2 spike protein, respectively. Interestingly, for the first time, experimental results suggested that navitoclax could be potentially applied to stop SARS-CoV-2 and remains to further validation.

Development of novel benzofuran-based SLC-0111 analogs as selective cancer-associated carbonic anhydrase isoform IX inhibitors.

In the present study, we describe the design of different series of benzofuran-based derivatives as potential carbonic anhydrase inhibitors (CAIs). The adopted design is based on bioisosteric replacement for the p-fluorophenyl SLC-0111 tail with the lipophilic 2-methylbenzofuran or 5-bromobenzofuran tails to furnish the 2-methylbenzofuran (MBF) sulfonamides (MBFS; 9, 11 and 13) and 5-bromobenzofuran (BBF) sulfonamides (BBFS; 27a-b, 28a-b and 29a-c), respectively. Thereafter, the urea spacer was either elongated to furnish MBFS (17 and 19), and BBFS (30) series, or replaced by a carbamate one to afford MBFS (15). All the designed compounds were synthesized and evaluated for their inhibitory activities against four human (h) CA isoforms: hCA I, II, IX and XII. MBFS (11b and 17) and BBFS (28b, 29a and 30) efficiently inhibited the tumor-related CA IX isoform in the single-digit nanomolar range (KIs = 8.4, 7.6, 5.5, 7.1 and 1.8 nM, respectively). In particular, MBFS 11b and BBFS 28b exhibited good selectivity toward hCA IX isoform over the main off-target hCA II isoform (S.I. = 26.4 and 58.9, respectively). As a consequence, 11b and 28b were examined for their anticancer and pro-apoptotic activities toward MDA-MB-231 and MCF-7 cancer cell lines.

Global retention models and their application to the prediction of chromatographic fingerprints.

The resolution of samples containing unknown compounds of different nature, or without standards available, as is the case of chromatographic fingerprints, is still a challenge. Possibly, the most problematic aspect that prevents systematic method development is finding models that describe without bias the retention behaviour of the compounds in the samples. In this work, the use of global models (able to describe the whole sample) is proposed as an alternative to the use of individual models for each solute. Global models contain parameters that are specific for each solute, while other parameters ‒related to the column and solvent‒ are common for all solutes. A special regression procedure is presented for the construction of global models, which are applied to predict highly complex chromatograms, such as chromatographic fingerprints, for diverse experimental conditions in isocratic and gradient elution. Another interesting application is the prediction of molecular properties, such as log Po/w, from the specific solute parameters of the global models. The examined adapted models are based on the equations proposed by Snyder, Schoenmakers, Neue and Kuss, Jandera, and Bosch Rosés to describe the retention. In all cases, the predictive capability was very satisfactory. Two cases of study were considered: chromatograms of camomile extracts analysed using acetonitrile gradients, and a set of 145 known compounds in a wide range of structures and functionalities, eluted isocratically with acetonitrile/water mobile phases.

Molecular Docking and Virtual Screening Based Prediction of Drugs for COVID-19.

AIMS: To predict potential drugs for COVID-19 by using molecular docking for virtual screening of drugs approved for other clinical applications. BACKGROUND: SARS-CoV-2 is the betacoronavirus responsible for the COVID-19 pandemic. It was listed as a potential global health threat by the WHO due to high mortality, high basic reproduction number, and lack of clinically approved drugs and vaccines. The genome of the virus responsible for COVID-19 has been sequenced. In addition, the three-dimensional structure of the main protease has been determined experimentally. OBJECTIVE: To identify potential drugs that can be repurposed for treatment of COVID-19 by using molecular docking based virtual screening of all approved drugs. METHODS: A list of drugs approved for clinical use was obtained from the SuperDRUG2 database. The structure of the target in the apo form, as well as structures of several target-ligand complexes, were obtained from RCSB PDB. The structure of SARS-CoV-2 Mpro determined from X-ray diffraction data was used as the target. Data regarding drugs in clinical trials for COVID-19 was obtained from clinicaltrials.org. Input for molecular docking based virtual screening was prepared by using Obabel and customized python, bash, and awk scripts. Molecular docking calculations were carried out with Vina and SMINA, and the docked conformations were analyzed and visualized with PLIP, Pymol, and Rasmol. RESULTS: Among the drugs that are being tested in clinical trials for COVID-19, Danoprevir and Darunavir were predicted to have the highest binding affinity for the Main protease (Mpro) target of SARS-CoV-2. Saquinavir and Beclabuvir were identified as the best novel candidates for COVID-19 therapy by using Virtual Screening of drugs approved for other clinical indications. CONCLUSION: Protease inhibitors approved for treatment of other viral diseases have the potential to be repurposed for treatment of COVID-19.

A Novel Series of [1,2,4]Triazolo[4,3-a]Pyridine Sulfonamides as Potential Antimalarial Agents: In Silico Studies, Synthesis and In Vitro Evaluation.

For the development of new and potent antimalarial drugs, we designed the virtual library with three points of randomization of novel [1,2,4]triazolo[4,3-a]pyridines bearing a sulfonamide fragment. The library of 1561 compounds has been investigated by both virtual screening and molecular docking methods using falcipain-2 as a target enzyme. 25 chosen hits were synthesized and evaluated for their antimalarial activity in vitro against Plasmodium falciparum. 3-Ethyl-N-(3-fluorobenzyl)-N-(4-methoxyphenyl)-[1,2,4]triazolo[4,3-a]pyridine-6-sulfonamide and 2-(3-chlorobenzyl)-8-(piperidin-1-ylsulfonyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one showed in vitro good antimalarial activity with inhibitory concentration IC50 = 2.24 and 4.98 µM, respectively. This new series of compounds may serve as a starting point for future antimalarial drug discovery programs.

An overview of carbohydrate-based carbonic anhydrase inhibitors.

Carbonic anhydrases (CAs) are metalloenzymes responsible for the reversible hydration of carbon dioxide to bicarbonate, a fundamental reaction involved in various physiological and pathological processes. In the last decades, CAs have been considered as important drug targets for different pathologies such as glaucoma, epilepsy and cancer. The design of potent and selective inhibitors has been an outstanding goal leading to the discovery of new drugs. Among the different strategies developed to date, the design of carbohydrate-based CA inhibitors (CAIs) has emerged as a versatile tool in order to selectively target CAs. The insertion of a glycosyl moiety as a hydrophilic tail in sulfonamide, sulfenamide, sulfamate or coumarin scaffolds allowed the discovery of many different series of sugar-based CAIs, with relevant inhibitory results. This review will focus on carbohydrate-based CAIs developed so far, classifying them in glycosidic and glycoconjugated inhibitors based on the conjugation chemistry adopted.

Unconventional amino acids in medicinal chemistry: First report on taurine merged within carbonic anhydrase inhibitors.

This study reports the design, synthesis of a series of taurine containing benzenesulfonamide derivatives which were all screened in vitro against the physiological relevant human (h) expressed Carbonic Anhydrase (CA; EC 4.2.1.1) I, II, IX, XII isozymes. Compound 2, 5, 11-16 displayed superior inhibitory activities against the tumor associated hCA IX over the reference drug Acetazolamide (AAZ). Both hCA IX and XII isoforms were selectively inhibited only by compound 3, whereas the chloro-containing compound 12 was showed as the most selective and effective inhibitor profile for the CA IX isoforms. To the best of our knowledge the data reported herein are the first of this kind and introduce in the literature new compounds worth for future development within the Medicinal Chemistry field.

Danoprevir for the Treatment of Hepatitis C Virus Infection: Design, Development, and Place in Therapy.

On June 8, 2018, an NS3/4A protease inhibitor called danoprevir was approved in China to treat the infections of HCV genotype (GT) 1b - the most common HCV genotype worldwide. Based on phase 2 and 3 clinical trials, the 12-week regimen of ritonavir-boosted danoprevir (danoprevir/r) plus peginterferon alpha-2a and ribavirin offered 97.1% (200/206) of sustained virologic response at post-treatment week 12 (SVR12) in treatment-naïve non-cirrhotic patients infected with HCV genotype 1b. Adverse events such as anemia, fatigue, fever, and headache were associated with the inclusion of peginterferon alpha-2a and ribavirin in the danoprevir-based regimen. Moreover, drug resistance to danoprevir could be traced to amino acid substitutions (Q80K/R, R155K, D168A/E/H/N/T/V) near the drug-binding pocket of HCV NS3 protease. Despite its approval, the clinical use of danoprevir is currently limited to its combination with peginterferon alpha-2a and ribavirin, thereby driving its development towards interferon-free, ribavirin-free regimens with improved tolerability and adherence. In the foreseeable future, pan-genotypic direct-acting antivirals with better clinical efficacy and less adverse events will be available to treat HCV infections worldwide.

Discovery of novel integrase-LEDGF/p75 allosteric inhibitors based on a benzene scaffold.

We report herein the discovery of novel integrase-LEDGF/p75 allosteric inhibitors (INLAIs) based on a benzene scaffold 3. This scaffold can extend substituents from the C1 position unlike the common pyridine scaffolds 2. Structure-activity relationship studies showed that the sulfonamide linker at the C1 position was important for the antiviral activity. Interaction between sulfonamide and Q95 was observed by X-ray crystallography. Compound 31h showed more potent antiviral activity (EC50 (NL432) = 3.9 nM) than BI-224436 (EC50 (NL432) = 56 nM), suggesting the potential of the newly designed scaffold 3.

Xie2-64, a novel CB2 receptor inverse agonist, reduces cocaine abuse-related behaviors in rodents.

Cocaine abuse remains a public health threat around the world. There are no pharmacological treatments approved for cocaine use disorder. Cannabis has received growing attention as a treatment for many conditions, including addiction. Most cannabis-based medication development has focused on cannabinoid CB1 receptor (CB1R) antagonists (and also inverse agonists) such as rimonabant, but clinical trials with rimonabant have failed due to its significant side-effects. Here we sought to determine whether a novel and selective CB2R inverse agonist, Xie2-64, has similar therapeutic potential for cocaine use disorder. Computational modeling indicated that Xie2-64 binds to CB2R in a way similar to SR144528, another well-characterized but less selective CB2R antagonist/inverse agonist, suggesting that Xie2-64 may also have CB2R antagonist profiles. Unexpectedly, systemic administration of Xie2-64 or SR144528 dose-dependently inhibited intravenous cocaine self-administration and shifted cocaine dose-response curves downward in rats and wild-type, but not in CB2R-knockout, mice. Xie2-64 also dose-dependently attenuated cocaine-enhanced brain-stimulation reward maintained by optical stimulation of ventral tegmental area dopamine (DA) neurons in DAT-Cre mice, while Xie2-64 or SR144528 alone inhibited optical brain-stimulation reward. In vivo microdialysis revealed that systemic or local administration of Xie2-64 into the nucleus accumbens reduced extracellular dopamine levels in a dose-dependent manner in rats. Together, these results suggest that Xie2-64 has significant anti-cocaine reward effects likely through a dopamine-dependent mechanism, and therefore, deserves further study as a new pharmacotherapy for cocaine use disorder.

Sulfonamide Inhibitors of Human Carbonic Anhydrases Designed through a Three-Tails Approach: Improving Ligand/Isoform Matching and Selectivity of Action.

The "tail approach" has become a milestone in human carbonic anhydrase inhibitor (hCAI) design for various therapeutics, including antiglaucoma agents. Besides the classical hydrophobic/hydrophilic division of hCAs active site, several subpockets have been identified at the middle/outer active sites rim, which could be targeted to increase the CAI isoform selectivity. This postulate is explored here by three-tailed benzenesulfonamide CAIs (TTI) to fully exploit such amino acid differences among hCAs. In this proof-of-concept study, an extensive structure-activity relationship (SAR) study was carried out with 32 such benzenesulfonamides differing in tails combination that were assayed for hCAs I, II, IV, and XII inhibition. A structural study was undertaken by X-ray crystallography and in silico tools to assess the ligand/target interaction mode. The most active and selective inhibitors against isoforms implicated in glaucoma were assessed in a rabbit model of the disease achieving an intraocular pressure-lowering action comparable to the clinically used dorzolamide.