Inhibition Of Ca2 Research Articles

Abstract Tu047: Carbonic anhydrase inhibitors (CAIs) mitigate cardiac amyloid β pathology, attenuating neuro-signaling adverse remodeling and improving cardiac function in the Tg2676- AD mouse model.

FDA-approved carbonic anhydrase inhibitors (CAIs) have been shown to attenuate Aβ pathology, neurodegeneration, and cerebrovascular dysfunction in models of Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA), suggesting a key role for CAs as a novel and previously unexplored target for AD therapy. Amyloid-β accumulation severely impairs the cerebral neuro-signaling pathway with a progressive loss in neurotrophic factors (like BDNF), potentially also affecting the cardiac nervous system and culminating in lethal heart dysfunction. Yet, no studies have proposed the use of CAIs for treating and preventing the systemic and cardiac effects of amyloidosis and AD. Here, we explored for the first time, the protective effects of a chronic CAIs therapeutic regimen against cardiac amyloid pathology, neuronal fibers’ loss, and heart neurotrophic dysregulation in Tg2576 mice, a widely used model of AD and cerebral amyloidosis. Cardiac fibrosis enhancement along with progressive Aβ deposition in the heart seriously affected the cardiac neuro-signaling pathway culminating in a robust decline of BDNF expression associated with myocardial adrenergic nerve fibers and regenerated nerve endings impoverishment (stained with TH and GAP-43 respectively) in 13-month-old Tg2576 mice compared to age-matched WT littermates. These degenerative mechanisms severely compromised heart function, evidenced by a decline of both ejection fraction and fraction shortening percentage in Tg2576 animals. Accordingly, we observed that human Aβ40 or Aβ42 oligomers’ treatment drastically reduced BDNF and GAP-43 expression in human neuronal cells and human cardiomyocytes. Notably, long-term CAIs treatment in Tg2576 mice reduced Aβ accumulation in the heart tissue and reverted cardiac neuro-signaling pathway adverse remodeling, thus ameliorating heart function, as evidenced through speckle tracking-based strain echocardiography analysis. These in vivo results were validated by in vitro experiments both in neuronal and cardiac cells. These findings suggest a new beneficial role of CAIs in preventing the Aβ induced cardiovascular remodeling and neuro-signaling deregulation for the first time in the Tg2576 model of AD. Taken together with the positive effects of CAIs on cerebrovascular function and cognition, this study paves the way for future clinical trials aimed at repurposing FDA-approved CAIs to prevent and correct both central and peripheral pathologies induced by AD and amyloidosis.

Abstract Tu121: Investigating Mechanisms Of MCUB Inhibition Of Mitochondrial Calcium Uptake

The mitochondrial calcium uniporter mediates Ca 2+ entry into the matrix, and matches energetic supply to demand during cardiac activity. However, many cardiac diseases are characterized by mitochondrial Ca 2+ overload, such as ischemia/reperfusion (I/R) injury. The uniporter channel is typically formed by a tetramer of MCU subunits. These subunits have two transmembrane domains and create a pore lined with negative charges to allow rapid and selective Ca 2+ permeation. Intriguingly, many studies have shown that a close homolog, MCUB can potentially oligomerize with MCU subunits to alter the pore. When the tetramer is made of MCU Ca 2+ transmission is facilitated, but the presence of MCUB inhibits Ca 2+ intake through the channel, suggesting that it is a dominant negative subunit. Moreover, recent studies in animals subject to ischemic cardiovascular injury has revealed endogenous upregulation of the MCUB subunit, proposed as an endogenous mechanism to prevent Ca 2+ overload. Deletion of MCUB enhances activation and uptake when exposed to high Ca 2+ , making MCUB −/− cells prone to mitochondrial Ca 2+ overload and pore opening. Here, we investigate the mechanisms by which MCUB regulates the behavior of the channel, focusing on how MCUB may influence complex composition and regulate its targeting. For this study, we performed structure-function studies of reconstituted MCUB in MCU -/- MCUB -/- double knockout HEK 293T cells. Using modified MCUB constructs and a range of MCU to MCUB transfection ratios, we queried how many MCUB subunits can successfully incorporate into uniporter complex. We subsequently created a range of tetrameric concatemers featuring different ratios of MCU to MCUB, allowing us to observe that increasing amounts of MCUB incorporation lead to greater inhibition of mitochondrial Ca 2+ uptake. Finally, we examined whether replacing portions of MCUB with the corresponding MCU sequence was able to rescue Ca 2+ uptake, finding that these substitutions failed to significantly increase mitochondrial Ca 2+ uptake. Our findings clarify how MCUB incorporation into the uniporter complex leads to dominant-negative inhibition of mitochondrial Ca 2+ uptake.

Incidence of Acute Cystoid Macular Edema after Starting a Prostaglandin Analog Compared with Other Classes of Glaucoma Medications

PurposeThere is a longstanding belief that prostaglandin analogs (PGAs) may predispose patients with glaucoma to develop acute cystoid macular edema (CME). However, there is little solid evidence supporting this notion. The purpose of this study is to compare CME incidence rates among patients initiating treatment with different glaucoma medication classes. DesignDatabase study. Participants39948 patients who were newly prescribed glaucoma medications MethodsUsing data from 10 health systems contributing data to the Sight Outcomes Research Collaborative (SOURCE) Ophthalmology Data Repository, we identified all adults with glaucoma who had been newly started on a topical glaucoma medication. Patients with pre-existing documentation of macular edema were excluded. We assessed the incidence of CME among patients with glaucoma who were newly started on PGAs, topical beta blockers (BBs), alpha agonists (AAs), and carbonic anhydrase inhibitors (CAIs). Using multivariable logistic regression, and adjusting for sociodemographic factors, we assessed the odds of developing CME among patients prescribed each of the 4 glaucoma medication classes. We also performed a subset regression analysis including lens status as a co-variate. Main outcome measuresIncidence of CME within 3 months of initiating therapy with different topical glaucoma medications. ResultsAmong the 39,948 patients were newly treated with a topical glaucoma medication, 139 (0.35%) developed CME. The incidence of CME was 0.13%, 0.65%, 0.55%, 1.76% for users of PGAs, BBs, alpha agonists (AAs) and carbonic anhydrase inhibitors (CAIs), respectively. After adjusting for sociodemographic factors, users of topical BBs, AAs and CAIs had substantially higher odds of developing CME compared with PGA users (P<0.001 for all comparisons). The subset analysis also showed higher odds ratio of the non-PGA medication classes in association with CME. ConclusionsClinicians should reconsider the notion that PGAs carry a higher risk of CME versus other glaucoma medication classes. If additional studies support the findings of these analyses, clinicians may feel more comfortable prescribing PGAs to patients with glaucoma without fear they will predispose patients to CME.

Dual-enzyme inhibiting nanomedicines for enhanced cancer chemodynamic therapy by inducing intratumoral acidosis

Deficiency of endogenous hydrogen peroxide and insufficient intracellular acidity are usually two important factors limiting chemodynamic therapy (CDT). Here we report a glutathione-responsive nanomedicine that can provide a suitable environment for CDT by inhibiting dual-enzymes simultaneously. The nanomedicine is constructed by encapsulation of a novel hydrogen sulfide donor in nanomicelle assembled by glutathione-responsive amphiphilic polymer. In response to intracellular glutathione, the nanomedicine can efficiently release the active ingredients hydrogen sulfide, carbonic anhydrase inhibitor and ferrocene. The hydrogen sulfide can increase the concentrations of hydrogen peroxide and lactic acid by inhibiting catalase and enhancing glycolysis. The carbonic anhydrase inhibitor can further induce intratumoral acidosis by inhibiting the function of carbonic anhydrase IX. Therefore, the nanomedicine can provide more efficient reaction conditions for the ferrocene-mediated Fenton reaction to generate abundant toxic hydroxyl radicals. In vivo results show that the combination of enhanced CDT and acidosis can effectively inhibit tumor growth. This design of nanomedicine provides a promising dual-enzyme inhibiting strategy to enhance antitumor efficacy of CDT.

Somatostatin analogues as a treatment option for cystoid maculopathy in retinitis pigmentosa

AimsThis study aimed to evaluate the effectiveness of somatostatin analogues (SA) for cystoid maculopathy (CM) in retinitis pigmentosa (RP) patients.Materials and methodsIn this retrospective case series, clinical and imaging characteristics...

Controlling Protein Assembly with Superchaotropic Nano-Ions.

In living systems, protein assemblies have essential functions, serving as structural supports, transport highways for molecular cargo, and containers of genetic material. The construction of protein assemblies, which involves control over space and time, remains a significant challenge in biotechnology. Here, we show that anionic boron clusters, 3,3'-commo-bis[closo-1,2-dicarba-3-cobaltadodecaborane] (COSAN-), and halogenated closo-dodecarboranes (B12X122-, X = Η, Cl or I), described as super-chaotropic nano-ions, induce the formation of 2D assemblies of model proteins, myoglobin, carbonic anhydrase, and trypsin inhibitor. We found that the nano-ion concentration reversibly controls the size of the protein assemblies. Furthermore, the secondary structures of the proteins are only slightly affected by assembly formation. For myoglobin, the formation of these assemblies even prevents temperature denaturation, highlighting a preservation effect of nano-ions. Our study reveals that inorganic boron-based nano-ions act as a reversible molecular glue for proteins, providing a potential starting point for the further development of controlled protein assemblies.

Controlling Protein Assembly with Superchaotropic Nano‐Ions.

In living systems, protein assemblies have essential functions, serving as structural supports, transport highways for molecular cargo, and containers of genetic material. The construction of protein assemblies, which involves control over space and time, remains a significant challenge in biotechnology. Here, we show that anionic boron clusters, 3,3’‐commo‐bis[closo‐1,2‐dicarba‐3‐cobaltadodecaborane] (COSAN‐), and halogenated closo‐dodecarboranes (B12X122‐, X = Η, Cl or I), described as super‐chaotropic nano‐ions, induce the formation of 2D assemblies of model proteins, myoglobin, carbonic anhydrase, and trypsin inhibitor. We found that the nano‐ion concentration reversibly controls the size of the protein assemblies. Furthermore, the secondary structures of the proteins are only slightly affected by assembly formation. For myoglobin, the formation of these assemblies even prevents temperature denaturation, highlighting a preservation effect of nano‐ions. Our study reveals that inorganic boron‐based nano‐ions act as a reversible molecular glue for proteins, providing a potential starting point for the further development of controlled protein assemblies.

Tail-approach based design, synthesis, and molecular modeling of benzenesulfonamides carrying thiadiazole and urea moieties as novel carbonic anhydrase inhibitors.

We synthesized herein 16 compounds (SUT1-SUT16) as potential carbonic anhydrase (CA) inhibitors utilizing the tail-approach design. Based on this strategy, we connected benzenesulfonamide, the zinc-binding scaffold, to different urea moieties with the 1,3,4-thiadiazole ring as a linker. We obtained the target compounds by the reaction of 4-(5-amino-1,3,4-thiadiazol-2-yl)benzenesulfonamide with aryl isocyanates. Upon confirmation of their structures, the compounds were screened for their ability to inhibit the tumor-related human (h) isoforms human carbonic anhydrase (hCA) IX and XII, as well as the physiologically dominant hCA I and II. Most of the molecules demonstrated Ki values ≤ 10 nM with different selectivity profiles. The binding modes of SUT9, SUT10, and SUT5, the most effective inhibitors of hCA II, IX, and XII, respectively, were predicted by molecular docking. SUT16 (4-{5-[3-(naphthalen-1-yl)ureido]-1,3,4-thiadiazol-2-yl}benzenesulfonamide) was found to be the most selective inhibitor of the cancer-associated isoforms hCA IX and XII over the off-target isoforms, hCAI and II. The interaction dynamics and stability of SUT16 within hCA IX and XII were investigated by molecular dynamics simulations as well as dynophore analysis. Based on computational data, increased hydrophobic contacts and hydrogen bonds in the tail part of these molecules within hCA IX and XII were found as favorable interactions leading to effective inhibitors of cancer-related isoforms.

A comprehensive investigation of the anion inhibition profile of a β-carbonic anhydrase from Acinetobacter baumannii for crafting innovative antimicrobial treatments

This study refers to the intricate world of Acinetobacter baumannii, a resilient pathogenic bacterium notorious for its propensity at antibiotic resistance in nosocomial infections. Expanding upon previous findings that emphasised the bifunctional enzyme PaaY, revealing unexpected γ-carbonic anhydrase (CA) activity, our research focuses on a different class of CA identified within the A. baumannii genome, the β-CA, designated as 𝛽-AbauCA (also indicated as CanB), which plays a crucial role in the resistance mechanism mediated by AmpC beta-lactamase. Here, we cloned, expressed, and purified the recombinant 𝛽-AbauCA, unveiling its distinctive kinetic properties and inhibition profile with inorganic anions (classical CA inhibitors). The exploration of 𝛽-AbauCA not only enhances our understanding of the CA repertoire of A. baumannii but also establishes a foundation for targeted therapeutic interventions against this resilient pathogen, promising advancements in combating its adaptability and antibiotic resistance.

Gonioscopy-assisted transluminal trabeculotomy (GATT) with scleral or iris fixation for subluxated intraocular lenses and glaucoma.

This retrospective chart review aims to report a combined surgical approach of intraocular lens (IOL) fixation and gonioscopy-assisted transluminal trabeculotomy (GATT) for the treatment of subluxated IOLs and glaucoma or ocular hypertension. Charts of patients who underwent IOL fixation combined with GATT between November 2019 and July 2023 were reviewed. The main outcome measure was surgical success, defined as a well-centered IOL and an IOP of 18 mmHg or lower and either a 30% IOP reduction or a reduction in medications as compared to baseline. Complications and the need for reoperation were recorded. Eleven patients who underwent GATT with IOL fixation were included. The mean age was 80.45 years (range: 73-90). IOL subluxation was associated with pseudoexfoliation in all cases. Seven patients underwent scleral fixation, and four underwent iris fixation. The mean follow-up was 15.36 (range: 2.7-26.6) months. The success rate was 72.73%. The mean baseline IOP was 20.63 ± 6.56 mmHg on 2.81 ± 1.53 medications. Four patients were on oral carbonic-anhydrase inhibitor (CAI) before surgery. The mean IOP at the end of the follow-up was 13.86 ± 3.5 mmHg on 1.36 ± 1.57 medications, and none were on oral CAIs. No intraoperative complications occurred, and transient hyphema and vitreous hemorrhage were the most common postoperative complications. All patients had a well-centered IOL. No patients needed additional surgery for IOL position or IOP control. The mean corrected distance visual acuity was 0.634 ± 0.62 logMAR at baseline and 0.36 ± 0.38 at the end of follow-up. GATT can be combined with IOL fixation to the sclera or iris to effectively reduce IOP and medication usage.

Dual Inhibitors of P-gp and Carbonic Anhydrase XII (hCA XII) against Tumor Multidrug Resistance with Piperazine Scaffold.

A new series of piperazine derivatives were synthesized and studied with the aim of obtaining dual inhibitors of P-glycoprotein (P-gp) and carbonic anhydrase XII (hCA XII) to synergistically overcome the P-gp-mediated multidrug resistance (MDR) in cancer cells expressing the two proteins, P-gp and hCA XII. Indeed, these hybrid compounds contain both P-gp and hCA XII binding groups on the two nitrogen atoms of the heterocyclic ring. All compounds showed good inhibitory activity on each protein (P-gp and hCA XII) studied individually, and many of them showed a synergistic effect in the resistant HT29/DOX and A549/DOX cell lines which overexpress both the target proteins. In particular, compound 33 displayed the best activity by enhancing the cytotoxicity and intracellular accumulation of doxorubicin in HT29/DOX and A549/DOX cells, thus resulting as promising P-gp-mediated MDR reverser with a synergistic mechanism. Furthermore, compounds 13, 27 and 32 induced collateral sensitivity (CS) in MDR cells, as they were more cytotoxic in resistant cells than in the sensitive ones; their CS mechanisms were extensively investigated.

Dehydroabietylamine-substituted trifluorobenzene sulfonamide rhodamine B hybrids as anticancer agents overcoming drug resistance

Attachment of a conjugate assembled from a novel fluorinated carbonic anhydrase inhibitor and rhodamine B onto dehydroabietylamine (DHA) or cyclododecylamine led to first-in-class conjugates of good cytotoxicity; thereby IC50 values (from SRB assays; employed tumor cell lines A2780, A2780Cis, A549, HT29, MCF7, and non-malignant human fibroblasts CCD18Co) between 0.2 and 0.7 μM were found. Both conjugates showed similar cytotoxic activity but the dehydroabietylamine derived conjugate outperformed its cyclododecyl analog in terms of tumor cell/non-tumor cell selectivity. Both conjugates accumulate intracellular, and the DHA conjugate was able to overcome drug resistance which is effective independent of the expression status of carbonic anhydrase IX.

Sequential Blockade with Loop Diuretics and Acetazolamide: A Novel Strategy in Acute Heart Failure

Abstract Acute decompensated heart failure (HF) is the most common form of acute HF (AHF) and presents with systemic congestion due to left ventricular dysfunction with sodium and water retention. Diuretics are the mainstay of treatment for AHF, with loop diuretics being the first-line therapy. However, in some studies, patients who were given high doses of loop diuretics were discharged from the hospital with residual signs of volume overload. Combining acetazolamide, a carbonic anhydrase inhibitor, with loop diuretics has been shown to be beneficial as it increases the efficacy of loop diuretics and reduces the signs and symptoms of congestion. Further, it can be used for the prevention or treatment of diuretic resistance (DR). Sequential nephron blockade with acetazolamide has emerged as a novel strategy for the treatment of AHF to enhance the efficacy of loop diuretics and prevent DR. This review highlights the combination of acetazolamide with loop diuretics as an alternative and possibly more effective decongestive strategy option in AHF patients. Nevertheless, there is limited evidence to support this combination therapy, and further research is necessary to substantiate its use in AHF patients.

Investigation on the Crystal Structures of Molecules Related to 2‐(Benzylsulfinyl)Benzoic Acid, As a Support to the Studies on the Inhibition of Human Carbonic Anhydrases

AbstractA recent interest attaches to the derivatives of the (2‐benzylsulfinyl)benzoic acid as inhibitors of human carbonic anhydrases (hCAs), an action that can be applied in innovative therapies. A set of crystal structures of six sulfides and six enantiopure sulfoxides related to this scaffold, taken from the literature, or derived from the work on the asymmetric synthesis of sulfinyl compounds, is investigated. The lattice energies of these structures are estimated by means of the Crystal Explorer 21 program. The weak interactions building up the crystal structures are identified, and their contributions are analyzed in comparison with the calculated lattice energies. The most stable conformations in the solid phase are identified. It is worth observing that the sulfides of the scaffold under investigation behave almost in the same manner; on the other hand, the presence of the sulfinyl group of the sulfoxides adds complexity, that shall be taken into account in future docking calculations of these molecules with the hCAs enzymes.

Inhibitory Effect of Two Carbonic Anhydrases Inhibitors on the Activity of Major Cytochrome P450 Enzymes.

Both AW-9A (coumarin derivative) and WES-1 (sulfonamide derivative) were designed and synthesized as potential selective carbonic anhydrase inhibitors and were tested for anticancer activity. This study was undertaken to investigate their potential inhibitory effects on the major human cytochrome P450 (CYP) drug-metabolizing enzymes. Specific CYP probe substrates and validated analytical methods were used to measure the activity of the tested CYP enzymes. Furthermore, in silico simulations were conducted to understand how AW-9A and WES-1 bind to CYP2A6 at a molecular level. Molecular docking experiments were performed using the high-resolution X-ray structure, Protein Data Bank (PDB) ID: 2FDV for CYP2A6. CYP2E1-catalyzed chlorzoxazone-6'-hydroxylation was strongly inhibited by AW-9A and WES-1 with IC50 values of 0.084 µM and 0.101 µM, respectively. CYP2A6-catalyzed coumarin-7'-hydroxylation was moderately inhibited by AW-9A (IC50 = 4.2 µM). CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 enzymes were weakly or negligibly inhibited by both agents. Docking studies suggest elevated potential to block the catalytic activity of CYP2A6. These findings point to the feasibility of utilizing these agents as promising chemopreventive agents (owing to inhibition of CYP2E1), and AW-9A as a smoking cessation aid (owing to inhibition of CYP2A6). Additional in-vivo studies should be conducted to examine the impact of CYP2A6 and CYP2E1 inhibition on drug interactions with probe substrates of these enzymes.

Effect of topical brinzolamide on visual function and waveform in patients of infantile nystagmus syndrome: A randomized control trial.

To evaluate the effect of topical carbonic anhydrase inhibitor (brinzolamide) versus placebo on visual function and waveforms in infantile nystagmus syndrome (INS). Prospective, placebo-controlled, double-blind, cross-over study. Setting- A tertiary eye care center. Patients- Cases of idiopathic INS with and without abnormal head posture aged ≥10 years who had not received previous treatment for nystagmus. Intervention- Patients were randomized into two groups. Group 1 was given placebo for 3 months, and after a washout period of 7 days started on topical brinzolamide for the next 3 months. In group 2, the order was reversed. The drops were administered topically three times (every 8 hours) in both eyes. Outcome measure- Binocular best corrected visual acuity (BCVA) using the ETDRS chart, eXpanded nystagmus acuity function (NAFX) score and INS waveforms obtained from eye movement recordings, intraocular pressure (IOP) by Goldmann applanation tonometer, near stereopsis by TNO stereo test, and change in abnormal head posture before and after intervention in the null position. A total of 29 cases completed the study (23 with abnormal head posture; 6 without abnormal head posture). While brinzolamide shows improvement in visual acuity and NAFX score in idiopathic INS, its clinical significance needs further evidence.

Phthalazine Sulfonamide Derivatives as Carbonic Anhydrase Inhibitors. Synthesis, Biological and in silico Evaluation.

Carbonic Anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide involved in several biological processes. They show a wide diversity in tissue distribution and their subcellular localization. Twenty-two novel phthalazine derivatives were designed, synthesized, and evaluated against four human isoforms: hCA I, hCA II, hCA IX, and hCA XII. Compounds appeared to be very active mostly against hCA IX (7) and hCA I (6) isoforms being more potent than reference drug acetazolamide (AAZ). Some compounds appeared to be very selective with a selectivity index up to 13.8. Furthermore, docking was performed for some of these compounds on all isoforms to understand the possible interactions with the active site. Additionally, the most active compounds against hCA IX were subjected to cell viability assay. The anticancer activity of the compounds (3 a-d, 5 d, 5 i, and 5 m) was investigated using two human breast cancer cell lines, i. e. MCF-7 and MDA-MB-231 cells, and the normal counterpart, namely MCF10-A cells.

Development of a multi-targeted chemotherapeutic approach based on G-quadruplex stabilisation and carbonic anhydrase inhibition

A novel class of compounds designed to hit two anti-tumour targets, G-quadruplex structures and human carbonic anhydrases (hCAs) IX and XII is proposed. The induction/stabilisation of G-quadruplex structures by small molecules has emerged as an anticancer strategy, disrupting telomere maintenance and reducing oncogene expression. hCAs IX and XII are well-established anti-tumour targets, upregulated in many hypoxic tumours and contributing to metastasis. The ligands reported feature a berberine G-quadruplex stabiliser scaffold connected to a moiety inhibiting hCAs IX and XII. In vitro experiments showed that our compounds selectively stabilise G-quadruplex structures and inhibit hCAs IX and XII. The crystal structure of a telomeric G-quadruplex in complex with one of these ligands was obtained, shedding light on the ligand/target interaction mode. The most promising ligands showed significant cytotoxicity against CA IX-positive HeLa cancer cells in hypoxia, and the ability to stabilise G-quadruplexes within tumour cells.

Alkylation of morpholine and prolidine by phthalimide substituted Ru(II)–NHC catalysts

In this study, a series of benzimidazolium salts and silver-benimidazol-2-ylidene complexes were synthesized. The obtained silver complexes were converted into Ru(II)- benimidazol-2-ylidene complex using the transmetallation method. After elucidating the structures of these Ru(II)–NHC compounds, the synthesized ruthenium complexes were used in the alkylation reaction of cyclic amines to synthesize valuable derivatives such as pyrrolidine and morpholine. Pyrrolidine derivatives are extensively studied for their antimicrobial, antiviral, antifungal, anticancer, anti-inflammatory, anticonvulsant, cholinesterase inhibition, and carbonic anhydrase inhibition properties. Morpholine derivatives are particularly studied in the context of central nervous system (CNS) diseases. The yield of the catalytic products obtained was determined by GC. High selectivity and yield were achieved in the alkylation reactions of heterocyclic structures.

Synthesis, molecular docking and molecular dynamics simulations, drug-likeness studies, ADMET prediction and biological evaluation of novel pyrazole-carboxamides bearing sulfonamide moiety as potent carbonic anhydrase inhibitors.

Pyrazoles are unique bioactive molecules with a versatile biological profile and they have gained an important place on pharmaceutical chemistry. Pyrazole compounds containing sulfonamide nuclei also attract attention as carbonic anhydrase (CA) inhibitors. In this study, a library of pyrazole-carboxamides were synthesized and the structures of the synthesized molecules were characterized using FT-IR, 1H-NMR, 13C-NMR and HRMS. Then the inhibition effects of newly synthesized molecules on human erythrocyte hCA I and hCA II isoenzymes were investigated. Ki values of the compounds were in the range of 0.063-3.368µM for hCA I and 0.007-4.235µM for hCA II. Molecular docking studies were performed between the most active compounds 6a, 6b and the reference inhibitor, acetazolamide (AAZ) and the hCA I and hCA II receptors to investigate the binding mechanisms between the compounds and the receptors. These compounds showed better interactions than the AAZ. ADMET analyzes were performed for the compounds and it was seen that the compounds did not show AMES toxicity. The stability of the molecular docking results over time was analysed by 50ns molecular dynamics simulations. Molecular dynamics simulations revealed that 6a and 6b exhibited good stability after docking to the binding sites of hCA I and hCA II receptors, with minor conformational changes and fluctuations.