Quinazolinone-based benzenesulfonamides with low toxicity and high affinity as monoamine oxidase-A inhibitors: Synthesis, biological evaluation and induced-fit docking studies.

The research in selective monoamine oxidases (MAO-A and MAO-B) inhibitors has been increased due to their therapeutic value for neurodegenerative diseases. In this study, 4-((2-(aryl)-4-oxoquinazolin-3(4H)-yl)amino)benzenesulfonamides were synthesized and their MAOs inhibition potentials were investigated applying in vitro fluorometric technique. The most potent compounds 7 and 8 against MAO-A had IC50 values of 0.058 ± 0.002 and 0.094 ± 0.003 µM, respectively, while the reference moclobemide had an IC50 value of 6.061 µM. Compounds 7 (>1724 times) and 8 (>1063 times) more selective and reversible inhibitors of MAO-A rather than MAO-B. Toxicity studies of 7 (IC50 = 210.23 µM) and 8 (IC50 = 259.27 µM) showed that compounds can be considered as non-toxic towards SH-SY5Y cell line at their effective concentrations against MAO-A. In silico docking simulations successfully explained the observed activities and also highlighted structural water molecules to play a key role in the ligand-enzyme interactions. Calculated molecular descriptors are also obeying Lipinski's rule of five and brain/blood partition coefficients, a critical parameter in neurodegenerative diseases. These reversible inhibitors can have considerable advantages compared to irreversible inhibitors which may possess serious pharmacological side effects.

Investigation of carbonic anhydrase inhibitory effects and cytotoxicities of pyrazole-based hybrids carrying hydrazone and zinc-binding benzenesulfonamide pharmacophores.

Pyrazole-based carbohydrazone hybrids have been considered to be a remarkable class of compounds in pharmaceutical chemistry. Here, we reported bioactivities of 4-(3-(2-(arylidene)hydrazin-1-carbonyl)-5-phenyl-1H-pyrazol-1-yl)benzenesulfonamides (1-27) towards CA isoenzymes (hCA I, hCA II, hCA IX) and human oral squamous cell carcinoma cell line. Compounds 19 (Ki = 10.1 nM, hCA I/hCA IX = 749.6), 22 (Ki = 18.5 nM, hCA I/hCA IX = 429.2), 26 (Ki = 14.5 nM, hCA I/hCA IX = 596.9), 27 (Ki = 21.5 nM, hCA I/hCA IX = 413.1) were more potent and selective inhibitors of cancer-associated hCA IX isoenzyme. Compounds 22 and 26 were also found to be approximately three times more selective hCA IX inhibitors over off-target hCA II at low nanomolar. Compounds 19, 22, 23, 24, and 26 with IC50 of 1.6-1.7 µM showed potent cytotoxicity against human oral squamous cell carcinoma cell line as compared with human gingival fibroblast, producing the tumor-specificity value over 100. This was due to its cytostatic growth inhibition accompanied by a slight but significant dose-dependent increase in cell shrinkage and subG1 cell accumulation and marginal activation of caspase 3 substrates. Bioassay results showed that carbohydrazone-based hybrids could be useful candidates to design novel anticancer compounds and selective carbonic anhydrase inhibitors.

Exploring of tumor-associated carbonic anhydrase isoenzyme IX and XII inhibitory effects and cytotoxicities of the novel N-aryl-1-(4-sulfamoylphenyl)-5-(thiophen-2-yl)-1H-pyrazole-3-carboxamides.

A series of novel N-aryl-1-(4-sulfamoylphenyl)-5-(thiophen-2-yl)-1H-pyrazole-3-carboxamides was synthesized and examined as inhibitors of cytosolic (human) hCA I and hCA II, and cancer-related transmembrane hCA IX and hCA XII isoenzymes. AC2 was the most selective inhibitor towards cancer-related hCA IX while AC8 and AC9 selectively inhibited hCA XII over off-target isoenzymes. Anticancer effects of the compounds were evaluated towards human oral squamous cell carcinoma (OSCC) cell lines, human mesenchymal normal oral cells, breast (MCF7), prostate (PC3), non-small cell lung carcinoma cells (A549), and non-tumoral fetal lung fibroblast cells (MRC5). Compounds moderately showed cytotoxicity towards cancer cell lines. Among others, AC6 showed cell-specific cytotoxic activity and induced apoptosis in a dose-dependent manner without a significant change in the cell cycle distribution of MCF7. These results suggest that pyrazole-3-carboxamides need further molecular modification to increase their anticancer drug candidate potency.

Synthesis, structure elucidation, and in vitro pharmacological evaluation of novel polyfluoro substituted pyrazoline type sulfonamides as multi-target agents for inhibition of acetylcholinesterase and carbonic anhydrase I and II enzymes.

A novel series of 4-(3-(difluorophenyl)-5-(dimethoxyphenyl)-4,5-dihydropyrazol-1-yl)benzenesulfonamides 1-8 were designed since sulfonamide and pyrazoline pharmacophores draw great attention in novel drug design due to their wide range of bioactivities including acetylcholinesterase (AChE) and human carbonic anhydrase I and II (hCA I and hCA II) inhibitory potencies. Comprehensive structure elucidation of the compounds synthesized was carried out by 1H NMR, 13C NMR, 19F NMR, DEPT 90-135, 1H-1H COSY, 1H-13C HMQC, HMBC, and HRMS spectra. The chemical shifts and splitting patterns of the protons and carbons were affected by the fluorine atoms and exciting splitting patterns were also recorded for the fluorinated compounds. In vitro enzyme assays obviously showed that the novel compounds had a significant inhibitory profile against hCA I, hCA II and AChE enzymes at the nanomolar levels. Ki values were in the range of 3.30 ± 1.09-5.95 ± 2.26 nM for hCA I and 4.29 ± 0.91-7.14 ± 3.15 nM for hCA II, while Ki values for AChE were in the range of 3.28 ± 1.47-9.77 ± 1.86 nM. Many of thecompounds in this study can be considered as promising AChE and CA inhibitors.

Synthesis, biological evaluation and in silico modelling studies of 1,3,5-trisubstituted pyrazoles carrying benzenesulfonamide as potential anticancer agents and selective cancer-associated hCA IX isoenzyme inhibitors.

Inhibition of carbonic anhydrases (CAs, EC 4.2.1.1) has clinical importance for the treatment of several diseases. They participate in crucial regulatory mechanisms for balancing intracellular and extracellular pH of the cells. Among CA isoforms, selective inhibition of hCA IX has been linked to decreasing of cell growth for both primary tumors and metastases. The discovery of novel CA inhibitors as anticancer drug candidates is a current topic in medicinal chemistry. 1,3,5-Trisubstituted pyrazoles carrying benzenesulfonamide were evaluated against physiologically abundant cytosolic hCA I and hCA II and trans-membrane, tumor-associated hCA IX isoforms by a stopped-flow CO2 hydrase method. Their in vitro cytotoxicities were screened against human oral squamous cell carcinoma (OSCC) cell lines (HSC-2) and human mesenchymal normal oral cells (HGF) via 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) test. Compounds 6, 8, 9, 11, and 12 showed low nanomolar hCA II inhibitory potency with Ki < 10 nM, whereas compounds 9 and 12 displayed Ki < 10 nM against hCA IX isoenzyme when compared with reference Acetazolamide (AZA). Compound 9, 4-(3-(hydrazinecarbonyl)-5-(4-nitrophenyl)-1H-pyrazol-1-yl)benzenesulfonamide, can be considered as the most selective hCA IX inhibitor over off-target cytosolic isoenzymes hCA I and hCA II with the lowest Ki value of 2.3 nM and selectivity ratios of 3217 (hCA I/hCA IX) and 3.9 (hCA II/hCA IX). Isoform selectivity profiles were also discussed using in silico modelling. Cytotoxicity results pointed out that compounds 5 (CC50 = 37.7 µM) and 11 (CC50 = 58.1 µM) can be considered as lead cytotoxic compounds since they were more cytotoxic than 5-Fluorouracil (5-FU) and Methotrexate (MTX).

Synthesis and bioactivities of pyrazoline benzensulfonamides as carbonic anhydrase and acetylcholinesterase inhibitors with low cytotoxicity.

4-(3-Substitutedphenyl-5-polymethoxyphenyl-4,5-dihydro-1H-pyrazol-1-yl)benzenesulfonamides (9-16) were synthesized and their chemical structures were elucidated by 1H NMR, 13C NMR, and HRMS. The compounds designed include pyrazoline and sulfonamide pharmacophores in a single molecule by hibrit molecule approach which is a useful technique in medicinal chemistry in designing new compounds with potent activity for the desired several bioactivities. Inhibition potency of the sulfonamides were evaluated against human CA isoenzymes (hCA IandhCA II) and acetylcholinesterase (AChE) enzyme and also their cytotoxicities were investigated towards oral squamous cancer cell carcinoma (OSCC) cell lines (Ca9-22, HSC-2, HSC-3, and HSC-4) and non-tumor cells (HGF, HPLF, and HPC). Cytosolic hCA I and hCA II isoenzymes were inhibited by the sulfonamide derivatives (9-16) and Ki values were found in the range of 27.9 ±â€¯3.2-74.3 ±â€¯28.9 nM and 27.4 ±â€¯1.4-54.5 ±â€¯11.6 nM, respectively. AChE enzyme was strongly inhibited by the sulfonamide derivatives with Ki values in the range of 37.7 ±â€¯14.4-89.2 ±â€¯30.2 nM The CC50 values of the compounds were found between 15 and 200 µM towards OSCC malign cell lines. Their tumor selectivities were also calculated with two ways. Compound's selectivities towards cancer cell line were found generally low, except compounds bearing 3,4-dimethoxyphenyl 14 (TS1 = 1.3, TS2 = 1.4) and 10 (TS2 = 1.4). All sulfonamide derivatives studied here can be considered as good candidates to develop novel CAs or AChE inhibitor candidates based on the enzyme inhibition potencies with their low cytotoxicity and tumor selectivity.

Anticancer effects of new dibenzenesulfonamides by inducing apoptosis and autophagy pathways and their carbonic anhydrase inhibitory effects on hCA I, hCA II, hCA IX, hCA XII isoenzymes.

In this study, new dibenzensulfonamides, 7-9, having the chemical structure 4,4'-(5'-chloro-3'-methyl-5-aryl-3,4-dihydro-1'H,H-[3,4'-bipyrazole]-1',2-diyl)dibenzenesulfonamide were synthesized in five steps to develop new anticancer drug candidates. Their chemical structures were confirmed by 1H NMR, 13C NMR and HRMS spectra. Cytotoxicities of the dibenzensulfonamides were investigated towards HCC1937, MCF7, HeLa, A549 as tumor cell lines and towards MRC5 and Vero as non-tumor cells. Carbonic anhydrase (CAs, EC 4.2.1.1) inhibitory effects of the dibenzensulfonamides 7-9 were also evaluated on the cytosolic human (h) hCA I and II and the tumor-associated hCA IX and XII isoenzymes. Results indicate that both 7 and 8 induced cleavage of poly (ADP ribose) polymerase (PARP), activation of caspases -3, -7 and -9 which are the hallmarks of apoptosis. Meanwhile both compounds induced autophagy in HCC1937 cells which is shown by enhanced expression of LC3 and decreased level of p62 protein. The compounds tested were also effectively inhibited tumor-associated hCA IX and hCA XII isoenzymes in the range of 20.7-28.1 nM and 4.5-9.3 nM, respectively.

Curcumin analogue 1,5-bis(4-hydroxy-3-((4-methylpiperazin-1-yl)methyl)phenyl)penta-1,4-dien-3-one mediates growth arrest and apoptosis by targeting the PI3K/AKT/mTOR and PKC-theta signaling pathways in human breast carcinoma cells.

Recent developments in the literature have demonstrated that curcumin exhibit antioxidant properties supporting its anti-inflammatory, chemopreventive and antitumoral activities against aggressive and recurrent cancers. Despite the valuable findings of curcumin against different cancer cells, the clinical use of curcumin in cancer treatment is limited due to its extremely low aqueous solubility and instability, which lead to poor in vivo bioavailability and limited therapeutic effects. We therefore focused in the present study to evaluate the anti-tumor potential of curcumin analogues on the human breast carcinoma cell lines MDA-MB-231 and MCF-7, as well as their effects on non-tumorigenic normal breast epithelial cells (MCF-10). The IC50 values of curcumin analogue J1 in these cancer cell lines were determined to be 5 ng/ml and 10 ng/ml, in MDA-MB-231 and MCF-7 cells respectively. Interestingly, at these concentrations, the J1 did not affect the viability of non-tumorigenic normal breast epithelial cells MCF-10. Furthermore, we found that J1 strongly induced growth arrest of these cancer cells by modulating the mitochondrial membrane potentials without significant effect on normal MCF-10 cells using JC-1 staining and flow cytometry analysis. Using annexin-V/PI double staining assay followed by flow cytometry analysis, we found that J1 robustly enhanced the induction of apoptosis by increasing the activity of caspases in MDA-MB-231 and MCF-7 cancer cells. In addition, treatment of breast cancer cells with J1 revealed that, in contrast to the expression of cyclin B1, this curcumin analogue vigorously decreased the expression of cyclin A, CDK2 and cyclin E and subsequently sensitized tumor cells to cell cycle arrest. Most importantly, the phosphorylation of AKT, mTOR and PKC-theta in J1-treated cancer cells was markedly decreased and hence affecting the survival of these cancer cells. Most interestingly, J1-treated cancer cells exhibited a significant inhibition in the activation of RhoA followed by reduction in actin polymerization and cytoskeletal rearrangement in response to CXCL12. Our data reveal the therapeutic potential of the curcumin analogue J1 and the underlying mechanisms to fight breast cancer cells.

New anticancer drug candidates sulfonamides as selective hCA IX or hCA XII inhibitors.

In this study, new 4-[3-(aryl)-5-substitutedphenyl-4,5-dihydro-1H-pyrazole-1-yl]benzensulfonamides (19-36) were synthesized and evaluated their cytotoxic/anticancer and CA inhibitory effects. According to results obtained, the compounds 34 (4-[5-(2,3,4-trimethoxyphenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-yl] benzensulfonamide, Potency-Selectivity Expression (PSE) = 141) and 36 (4-[5-(3,4,5-trimethoxyphenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-yl]benzensulfonamide, PSE = 54.5) were found the leader anticancer compounds with the highest PSE values. In CA inhibitory studies, the compounds 36 and 24 (4-[5-(3,4,5-trimethoxyphenyl)-3-(4-fluorophenyl)-4,5-dihydro-1H-pyrazole-1-yl]benzensulfonamide) were found the leader CA inhibitors depending on selectivity ratios. The compound 36 was a selective inhibitor of hCA XII isoenzyme (hCA I/hCA XII = 1250 and hCA II/hCA XII = 224) while the compound 24 was a selective inhibitor of hCA IX isoenzyme (hCA I/hCA IX = 161 and hCA II/hCA IX = 177). The compounds 24, 34, and 36 can be considered to develop new anticancer drug candidates.

Microwave-assisted synthesis and bioevaluation of new sulfonamides.

In this study, 4-[5-(4-hydroxyphenyl)-3-aryl-4,5-dihydro-1H-pyrazol-1-yl]benzenesulfonamide derivatives (8-14) were synthesized for the first time by microwave irradiation and their chemical structures were confirmed by 1H NMR, 13C NMR and HRMS. Cytotoxic activities and inhibitory effects on carbonic anhydrase I and II isoenzymes of the compounds were investigated. The compounds 9 (PSE = 4.2), 12 (PSE = 4.1) and 13 (PSE = 3.9) with the highest potency selectivity expression (PSE) values in cytotoxicity experiments and the compounds 13 (Ki = 3.73 ± 0.91 nM toward hCA I) and 14 (Ki = 3.85 ± 0.57 nM toward hCA II) with the lowest Ki values in CA inhibition studies can be considered as leader compounds for further studies.

Designing, synthesis and bioactivities of 4-[3-(4-hydroxyphenyl)-5-aryl-4,5-dihydro-pyrazol-1-yl]benzenesulfonamides.

In this study, 4-[3-(4-hydroxyphenyl)-5-aryl-4,5-dihydro-pyrazol-1-yl]benzenesulfonamide (1-9) types compounds were synthesized and their chemical structures were confirmed by 1H NMR, 13C NMR and HRMS spectra. Cytotoxic and carbonic anhydrase (CA) inhibitory effects of the compounds were investigated. Cytotoxicity experiments pointed out that compound 4, (4-[5-(4-chlorophenyl)-3-(4-hydroxyphenyl)-4,5-dihydro-pyrazol-1-yl]benzenesulfonamide), exerting the highest tumor selectivity (TS) and potency selectivity expression (PSE) values, can be considered as a lead compound of this study in terms of development of novel anticancer agents. All synthesized sulfonamides showed a good inhibition profile on hCA IX and XII in the range of 53.5-923 nM and 6.2-95 nM, respectively. These compounds were 2.5-13.4 times more selective for the inhibition of hCA XII versus hCA IX, except compound 2 which had similar inhibitory action towards both isoenzymes.

Synthesis of mono Mannich bases of 2-(4-hydroxybenzylidene)-2,3-dihydroinden-1-one and evaluation of their cytotoxicities.

Chalcones and Mannich bases are a group of compounds known for their cytotoxicities. In this study restricted chalcone analogue, compound 2-(4-hydroxybenzylidene)-2,3-dihydroinden-1-one MT1, was used as a starting compound to synthesize new mono Mannich bases since Mannich bases may induce more cytotoxicity than chalcone analogue that they are derived from by producing additional alkylating center for cellular thiols. In this study, cyclic and acyclic amines were used to synthesize Mannich bases. All compounds were tested against Ca9-22 (gingival carcinoma), HSC-2, HSC-3 and HSC-4 (oral squamous cell carcinoma) as tumour cell lines and HGF (gingival fibroblasts), HPC (pulp cells) and HPLF (periodontal ligament fibroblasts) human normal oral cells as non tumour cell lines. Cytotoxicity, selectivity index (SI) values and potency selectivity expression (PSE) values expressed as a percentage were determined for the compounds. According to data obtained, the compound MT8 with the highest PSE value bearing N-methylpiperazine moiety seems to be a good candidate to develop new cytotoxic compounds and is suited for further investigation.

Synthesis and bioactivities of halogen bearing phenolic chalcones and their corresponding bis Mannich bases.

Phenolic bis Mannich bases having the chemical structure of 1-[3,5-bis-aminomethyl-4-hydroxyphenyl]-3-(4-halogenophenyl)-2-propen-1-ones (1a-c, 2a-c, 3a-c) were synthesized (Numbers 1, 2, and 3 represent fluorine, chlorine, and bromine bearing compounds, respectively, while a, b, and c letters represent the compounds having piperidine, morpholine, and N-methyl piperazine) and their cytotoxic and carbonic anhydrase (CA, EC 4.2.1.1) enzyme inhibitory effects were evaluated. Lead compounds should possess both marked cytotoxic potencies and selective toxicity for tumors. To reflect this potency, PSE values of the compounds were calculated. According to PSE values, the compounds 2b and 3b may serve as lead molecules for further anticancer drug candidate developments. Although the compounds showed a low inhibition potency toward hCA I (25-43%) and hCA II (6-25%) isoforms at 10 µM concentration of inhibitor, the compounds were more selective (1.5-5.2 times) toward hCA I isoenzyme. It seems that the compounds need molecular modifications for the development of better CA inhibitors.

The inhibitory effects of phenolic Mannich bases on carbonic anhydrase I and II isoenzymes.

Phenolic mono Mannich bases [2-[4-hydroxy-3-(aminomethyl)benzylidene]-2,3-dihydro-1H-inden-1-one (8-15)] and bis Mannich bases [2-[4-hydroxy-3,5-bis(aminomethyl)benzylidene]-2, 3-dihydro-1H-inden-1-one (2-7)] were synthesized starting from 2-(4-hydroxybenzylidene)-2, 3-dihydro-inden-1-one (1). This study was designed in order to investigate the carbonic anhydrase (CA, EC 4.2.1.1) inhibitory properties of a library of compounds incorporating the phenol functional group. All prepared compounds showed a low inhibition percentages on both human (h) isoforms hCA I and hCA II compared to the reference sulfonamide acetazolamide. Mannich bases 2-15 had lower inhibition percentages than the compound 1 on hCA I and hCA II, except compound 14, which is a Mannich base derivative of dipropylamine, which had a similar inhibitory power as compound 1 on hCA II. All compounds synthesized 1-15 were 1.3-1.9 times more effective on hCA II comparing with the effectivenes of the compounds on hCA I.

Carbonic anhydrase inhibition and cytotoxicity studies of Mannich base derivatives of thymol.

Mannich bases of thymol were synthesized. The aminomethylation reaction was realised in the ortho position of the phenol for compounds 2 (dipropylamine), 3 (benzylamine), and 4 (dibenzylamine) while it was from para position for 1 (dimethylamine), 5 (piperidine), 6 (morpholine) and 7 (N-methylpiperazine). The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory effects of the compounds were asssessed against hCA I and hCA II. All compounds moderately inhibited hCA I and hCA II. The cytotoxicity of the compounds against four human oral squamous cell carcinoma cell lines were compared those against three normal oral cells. Tumor specificity values were about 2 or slightly more for the compounds 2, 3, 4, 5 and 6. Compound 2 showed cytostatic activity against OSCC cell lines at 16 to 32-fold lower concentrations as compared with normal cells. This suggests that compound 2 can be considered as cytotoxicity enhancing drug candidate for further investigations.

Inhibitory effects of isatin Mannich bases on carbonic anhydrases, acetylcholinesterase, and butyrylcholinesterase.

The effects of isatin Mannich bases incorporating (1-[piperidin-1-yl (P1)/morpholin-4-yl (P2)/N-methylpiperazin-1-yl (P3)]methyl)-1H-indole-2,3-dione) moieties against human (h) carbonic anhydrase (CA, EC 4.2.1.1) isoenzymes hCA I and hCA II, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) enzymes were evaluated. P1-P3 demonstrated impressive inhibition profiles against AChE and BChE and also inhibited both CAs at nanomolar level. These inhibitory effects were more powerful in all cases than the reference compounds used for all these enzymes. This study suggests that isatin Mannich bases P1-P3 are good candidate compounds especially for the development of new cholinesterase inhibitors since they were 2.2-5.9 times better inhibitors than clinically used drug Tacrine.

Synthesis of 4-(2-substituted hydrazinyl)benzenesulfonamides and their carbonic anhydrase inhibitory effects.

In this study, 4-(2-substituted hydrazinyl)benzenesulfonamides were synthesized by microwave irradiation and their chemical structures were confirmed by (1)H NMR, (13)CNMR, and HRMS. Ketones used were: Acetophenone (S1), 4-methylacetophenone (S2), 4-chloroacetophenone (S3), 4-fluoroacetophenone (S4), 4-bromoacetophenone (S5), 4-methoxyacetophenone (S6), 4-nitroacetophenone (S7), 2-acetylthiophene (S8), 2-acetylfuran (S9), 1-indanone (S10), 2-indanone (S11). The compounds S9, S10 and S11 were reported for the first time, while S1-S8 was synthesized by different method than literature reported using microwave irradiation method instead of conventional heating in this study. The inhibitory effects of 4-(2-substituted hydrazinyl)benzenesulfonamide derivatives (S1-S11) against hCA I and II were studied. Cytosolic hCA I and II isoenzymes were potently inhibited by new synthesized sulphonamide derivatives with Kis in the range of 1.79 ± 0.22-2.73 ± 0.08 nM against hCA I and in the range of 1.72 ± 0.58-11.64 ± 5.21 nM against hCA II, respectively.

Synthesis, cytotoxicity and carbonic anhydrase inhibitory activities of new pyrazolines.

A series of polymethoxylated-pyrazoline benzene sulfonamides were synthesized, investigated for their cytotoxic activities on tumor and non-tumor cell lines and inhibitory effects on carbonic anhydrase isoenzymes (hCA I and hCA II). Although tumor selectivity (TS) of the compounds were less than the reference compounds 5-Fluorouracil and Melphalan, trimethoxy derivatives 4, 5, and 6 were more selective than dimethoxy derivatives 2 and 3 as judged by the cytotoxicity assay with the cells both types originated from the gingival tissue. The compound 6 (4-[3-(4-methoxyphenyl)-5-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl] benzene sulfonamide) showed the highest TS values and can be considered as a lead molecule of the series for further investigations. All compounds synthesized showed superior CA inhibitory activity than the reference compound acetazolamide on hCA I, and II isoenzymes, with inhibition constants in the range of 26.5-55.5 nM against hCA I and of 18.9-28.8 nM against hCA II, respectively.

Pharmaceutical Studies on Piperazine-Based Compounds Targeting Serotonin Receptors and Serotonin Reuptake Transporters.

Depression is a debilitating mental illness that has a significant impact on an individual's psychological, social, and physical life. Multiple factors, such as genetic factors and abnormalities in neurotransmitter levels, contribute to the development of depression. Monoamine oxidase inhibitors, tricyclic antidepressants, serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors, and atypical and new-generation antidepressants are well-known drug classes. SSRIs are the commonly prescribed antidepressant medications in the clinic. Genetic variations impacting serotonergic activity in people can influence susceptibility to diseases and response to antidepressant therapy. Gene polymorphisms related to 5-hydroxytryptamine (5-HT) signaling and subtypes of 5-HT receptors may play a role in the development of depression and the response to antidepressants. SSRIs binding to 5-HT reuptake transporters help relieve depression symptoms. Research has been conducted to identify a biomarker for detecting depressive disorders to identify new treatment targets and maybe offer novel therapy approaches. The pharmacological potentials of the piperazine-based compounds led researchers to design new piperazine derivatives and to examine their pharmacological activities. Structure-activity relationships indicated that the first aspect is the flexibility in the molecules, where a linker of typically a 2-4 carbon chain joins two aromatic sides, one of which is attached to a piperazine/phenylpiperazine/benzyl piperazine moiety. Newly investigated compounds having a piperazine core show a superior antidepressant effect compared to SSRIs in vitro/in vivo.

Synergistic quantification of mixed insulin preparations using time domain NMR techniques.

Diabetes patients often rely on tailored insulin therapies, necessitating precise blends of various insulin types to achieve optimal pharmacokinetic profiles, including the quantity and action duration of insulin absorption into the bloodstream. This study aimed to develop an accurate quantification method for mixed insulin preparations, consisting of Insulin-NPH and Insulin Regular in ratios varying between 0:100-100:0. Time Domain NMR (TD-NMR) techniques, T2 relaxation times, and T1T2 maps were used to analyze the mixtures. Individually, neither technique provided a reliable determination of insulin ratios. However, the integration of both methods through chemometrics has been proven to be a synergistic approach, yielding a robust quantification technique suitable for quality control in the assessment of mixed insulin drugs. This innovative combined TD-NMR method is non-invasive, cost-effective, and user-friendly, offering at the same time a significant potential for preventing health complications associated with improper insulin dosing. Furthermore, our work elucidates the broader applicability of converging multiple TD-NMR techniques for analyzing intricate mixtures.