Repurposing of Strychnine as the Potential Inhibitors of Aldo-keto Reductase Family 1 Members B1 and B10: Computational Modeling and Pharmacokinetic Analysis.

AKR1B1 and AKR1B10 are important members of aldo-keto reductase family which plays a significant role in cancer progression by modulating cellular metabolism. These enzymes are involved in various metabolic processes, including the synthesis and metabolism of hormones, detoxification of reactive aldehydes, and the reduction of various endogenous and exogenous compounds. This study aimed to explore the potential of strychnine as an anticancer agent by targeting AKR1B1 and AKR1B10 via drug repurposing approach. To assess the drug-like properties of strychnine, a physiologically based pharmacokinetic (PKPB) model and High Throughput Pharmacokinetics (HTPK) approach were employed. The obtained results fell within the expected range for drug molecules, confirming its suitability for further investigation. Additionally, density functional theory (DFT) studies were conducted to gain insight into the electronic properties contributing to the drug molecule's reactivity. Building upon the promising DFT results, molecular docking analysis using the AutoDock tool was performed to examine the binding interactions between strychnine and the proposed targets, AKR1B1 and AKR1B10. Findings from the molecular docking studies suggested a higher probability of strychnine acting as an inhibitor of AKR1B1 and AKR1B10 with docking scores of - 30.84 and - 29.36 kJ/mol respectively. To validate the stability of the protein-ligand complex, Molecular Dynamic Simulation (MDS) studies were conducted, revealing the formation of a stable complex between the enzymes and strychnine. This comprehensive approach sheds light on the potential effectiveness of strychnine as a treatment for breast, lung, liver, and pancreatic cancers, as well as related malignancies. The novel insights gained from the physiologically based pharmacokinetic modeling, density functional theory, molecular docking, and molecular dynamics simulations collectively support the prospect of strychnine as a promising molecule for anticancer therapy. Further investigations are warranted to validate these findings and explore the therapeutic potential of strychnine in preclinical and clinical settings.

Highly sensitive fluorescent probes for selective detection of hypochlorite: Applications in blood serum and cell imaging.

Being one of the vital reactive oxygen species (ROS), abnormal level of hypochlorite ion (ClO-) may pose detrimental threats to living organisms. Therefore, highly selective, and rapid monitoring of ClO- in living system is of prime importance to protect living organisms from its harmful effects. In this regard, design of synthetic fluorescent probes for ClO- has garnered considerable attention. However less fluorescence emission in aggregated state and less photostability of several existing probes for ClO- inspired us to design aggregation induced emission (AIE) active fluorescent probes SH1 and SH2. Probes were rationally designed by introducing thiourea moiety that selectively reacted through desulfurization reaction and resulted in highly selective detection of ClO-. Hypochlorite induced desulfurization reaction was validated through 1H NMR titration and DFT studies. Fine tuning of probes SH1 and SH2 prompted highly sensitive nanoscale (55 nM and 77 nM) and rapid (15 and 35 sec) detection of ClO-. Probe SH1 displayed less cytotoxic effect to live cells before it was successfully applied for bioimaging of ClO- in live MCF-7 cells. Moreover, probes displayed excellent sensing potential for ClO- in blood serum and real water samples. Advantageously, probe coated portable fluorescent films were fabricated for the easy and fast monitoring of ClO-. Of note, this work offers excellent design strategy for highly selective detection of ClO- that may lead to clinical trials.

Ratiometric and colorimetric probes with large stokes shift for sensing of exogenous hypochlorite in potato sprouts and industrial effluents.

Being one of the important reactive oxygen species (ROS), hypochlorite ions (ClO-) are involved in the control of several pathological and physiological processes. However, overexpression of ClO- may prompt several disorders including cancer. Therefore, two fluorescein functionalized compounds with catechol (probe 1) and 2-naphthyl (probe 2) as substituents were synthesized through Schiff base reaction to recognize ClO- in food items and industrial samples. While probe 2 exhibited turn-off fluorescent response towards ClO- with limit of detection (LOD) of 86.7 nM, structurally alike probe 1 showed excellent ratiometric response with low detection limit (36.3 nM), large Stokes shift (353 nm), and 'fast' response time (15 s). 1H NMR titration experiments favored spiroring opening of probe 1 upon the reaction with ClO-. Probe 1 was successfully utilized for the monitoring of exogenous ClO- in industrial samples. Further, fabrication of probe coated fluorescent paper strips and recognition of ClO- in sprouting potato show diverse practical applicability of our probes.

Synthesis, kinetic studies and in-silico investigations of novel quinolinyl-iminothiazolines as alkaline phosphatase inhibitors.

Deposition of hydroxyapatite (HA) or alkaline phosphate crystals on soft tissues causes the pathological calcification diseases comprising of end-stage osteoarthritis (OA), ankylosing spondylitis (AS), medial artery calcification and tumour calcification. The pathological calcification is symbolised by increased concentration of tissue non-specific alkaline phosphatase (TNAP). An efficient therapeutic strategy to eradicate these diseases is required, and for this the alkaline phosphatase inhibitors can play a potential role. In this context a series of novel quinolinyl iminothiazolines was synthesised and evaluated for alkaline phosphatase inhibition potential. All the compounds were subjected to DFT studies where N-benzamide quinolinyl iminothiazoline (6g), N-dichlorobenzamide quinolinyl iminothiazoline (6i) and N-nitrobenzamide quinolinyl iminothiazoline (6j) were found as the most reactive compounds. Then during the in-vitro testing, the compound N-benzamide quinolinyl iminothiazoline (6g) exhibited the maximum alkaline phosphatase inhibitory effect (IC50 = 0.337 ± 0.015 µM) as compared to other analogues and standard KH2PO4 (IC50 = 5.245 ± 0.477 µM). The results were supported by the molecular docking studies, molecular dynamics simulations and kinetic analysis which also revealed the inhibitory potential of compound N-benzamide quinolinyl iminothiazoline (6g) against alkaline phosphatase. This compound can be act as lead molecule for the synthesis of more effective inhibitors and can be suggested to test at the molecular level.

AIEE active sensors for fluorescence enhancement based detection of Ni2+ in living cells: Mechanofluorochromic and photochromic properties with reversible sensing of acid and base.

Stimuli responsive sensors QI 1 and QI 2 were rationally developed which exhibited diverse features of mutable mechanofluorochromism, reversible photochromism, solvatochromism, aggregation induced emission enhancement (AIEE), and metal ion sensing. After observing the exceptional structural property relationship, sensors were applied for reversible colorimetric and fluorometric determination of Ni2+ with low detection limits of 12 and 17 nM, respectively. Fluorescence emission enhancement based Ni2+ sensing was induced by chelation enhanced fluorescence (CHEF) mechanism. CHEF is triggered by the inhibition of excited state intramolecular proton transfer (ESIPT) and -C=N isomerization. The proposed Ni2+ sensing mechanism was investigated through 1H NMR, FT-IR titration, theoretical studies, and Jobs plots. Further, the developed sensors successfully demonstrated the selective acid-base induced absorption/emission switching through reversible ring-opening/closing and keto-enol tautomerization, evidenced by 1H NMR titration experiments. Additionally, the sensitivity of the sensor QI 1 towards Ni2+ was effectively mimicked in live MCF-7 cells and industrial effluents. Furthermore, monitoring of Ni2+ ions was also accessed through inexpensive and portable sensors' coated fluorescent films. Finally, an INHIBIT logic gate was fabricated imputing Ni2+ and EDTA as input signals to electronically scrutinize the targeted Ni2+.

Design, Synthesis, Kinetic Analysis and Pharmacophore-Directed Discovery of 3-Ethylaniline Hybrid Imino-Thiazolidinone as Potential Inhibitor of Carbonic Anhydrase II: An Emerging Biological Target for Treatment of Cancer.

Carbonic anhydrases (CA), having Zn2+ metal atoms, are responsible for the catalysis of CO2 and water to bicarbonate and protons. Any abnormality in the functioning of these enzymes may lead to morbidities such as glaucoma and different types of cancers including brain, renal and pancreatic carcinomas. To cope with the lack of presence of a promising therapeutic agent against these cancers, searching for an efficient and suitable carbonic anhydrase inhibitor is crucial. In the current study, ten novel 3-ethylaniline hybrid imino-thiazolidinones were synthesized and characterized by FTIR, NMR (1H, 13C), and mass spectrometry. Synthesis was carried out by diethyl but-2-ynedioate cyclization and different acyl thiourea substitutions of 3-ethyl amine. The CA (II) enzyme inhibition profile for all synthesized derivatives was determined. It was observed that compound 6e demonstrated highest inhibition of CA-II with an IC50 value of 1.545 ± 0.016 µM. In order to explore the pharmacophoric properties and develop structure activity relationship, in silico screening was performed. In silico investigations included density functional theory (DFT) studies, pharmacophore-guided model development, molecular docking, molecular dynamic (MD) simulations, and prediction of drug likeness scores. DFT investigations provided insight into the electronic characteristics of compounds, while molecular docking determined the binding orientation of derivatives within the CA-II active site. Compounds 6a, 6e, and 6g had a reactive profile and generated stable protein-ligand interactions with respective docking scores of -6.12, -6.99, and -6.76 kcal/mol. MD simulations were used to evaluate the stability of the top-ranked complex. In addition, pharmacophore-guided modeling demonstrated that compound 6e produced the best pharmacophore model (HHAAARR) compared to standard brinzolamide. In vitro and in silico investigations anticipated that compound 6e would be an inhibitor of carbonic anhydrase II with high efficacy. Compound 6e may serve as a potential lead for future synthesis that can be investigated at the molecular level, and additional in vivo studies are strongly encouraged.

Synthesis, characterization, SAR, antioxidant, anti-acetylcholinesterase and anti-butyrylcholinesterase activities of cephradine Schiff bases.

The objective of this study was to deal with the evaluation of 7-(2-(benzylideneamino)-2-(cyclohexa-1,4-dienyl)acetamido)-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid based schiff bases as a new class of enzyme inhibitors. In this connection, a series of Schiff bases of cephradine with substituted aromatic aldehydes was synthesized and characterized using FTIR, 1HNMR and 13CNMR. The in-vitro biological activities including free radical scavenging potential using DPPH assay, acetyl cholinesterase and butyryl cholinesterase inhibition potential were evaluated. Two compounds of the series 1g and 1h were found to be active against AChE whereas no derivative was active against BChE while the whole series showed excellent 1, 1-diphenyl-2-picrylhydrazyl scavenging activity. All the synthesized compounds were found to be non-toxic and present passive gastrointestinal absorption. Furthermore, the study suggests that the synthesized cephradine derivatives exhibit inhibitory potential against different biologically relevant enzyme targets.

Bio-oriented synthesis of new sulphadiazine derivatives for urease inhibition and their pharmacokinetic analysis.

Current research is based on biology-oriented synthesis of sulphadiazine derivatives and determination of their urease inhibitory activity. In this regard, a series of (E)-4-(benzylideneamino)-N-(pyrimidin-2-yl)benzenesulfonamide was synthesized from sulphadiazine and substituted aromatic aldehydes. The structures of synthesized compounds were ascertained by spectroscopic techniques, such as, FTIR, NMR and HRMS analysis, and in-vitro and in-silico investigation were carried out for the inhibition of urease. Ureases are harmful for humans by producing by-products of urea (ammonia and carbon dioxide). The most active compound (3l) against urease exhibited IC50 value of 2.21 ± 0.45 µM which is 10 times more potent than the standard thiourea (20.03 ± 2.06 µM). It is noteworthy that most of our synthesized compounds showed significant to excellent activities against urease enzyme and most of them substituted by halogen or hydroxy groups at ortho and para positions in their structures. Inhibition of enzyme by the synthesized analogues was in descending order as 3l > 3a > 3b > 3q > 3e > 3o > 3s > 3t > 3g > 3k > 3r > 3f > 3m > 3p > 3n > 3j > 3i > 3h. Moreover, molecular docking studies were performed to rationalize the binding interactions of the synthesized motifs with the active pocket of the urease enzyme. The synthesized sulphadiazine derivatives (3a-u) were found to be non-toxic, and presented passive gastrointestinal absorption.

Schiff bases of sulphonamides as a new class of antifungal agent against multidrug-resistant Candida auris.

Invasive Candida infections in hospitalized and immunocompromised or critically ill patients have become an important cause of morbidity and mortality. There are increasing reports of multidrug resistance in several Candida species that cause Candidemia, including C. glabrata and C. auris, with limited numbers of antifungal agents available to treat patients with invasive Candida infections. Therefore, there is an urgent need to discover new antifungal agents that work against multidrug-resistant Candida species, particularly C. auris, which has been identified as an emerging global pathogen. In this article, we report a new class of antifungal agents, the Schiff bases of sulphonamides, that show activity against all Candida species tested, with an MIC range of 4-32 µg/ml. Compound 2b showed activity against C. glabrata and a panel of fluconazole-resistant C. auris strains, with MICs of 4-16 µg/ml. The drug-like nature of these Schiff bases offers opportunities to optimize these compounds with medicinal chemistry techniques to obtain more potent analogs that can be progressed toward pre-clinical evaluation.

Probing sulphamethazine and sulphamethoxazole based Schiff bases as urease inhibitors; synthesis, characterization, molecular docking and ADME evaluation.

In the current study, a novel series of Schiff base derivatives of (E)-4-(benzylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide (3a-3f) and (E)-4-(benzylideneamino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide (3g-3q) were synthesize. The structures of synthetic compounds were elucidated by various spectroscopic techniques such as FTIR, NMR and spectrometric HRMS analysis. Synthetic derivatives were evaluated for their Jack Bean urease inhibitory activity using established in-vitro assay. It is worth mentioning here that most of our derivatives of both series displayed moderate to strong inhibitory activity, ranging between IC50 = 2.48 ± 0.78 µM and 35.63 ± 1.26 µM, as compared to standard thiourea (IC50 = 20.03 ± 2.03 µM). Further, structure activity relationship studies suggest that the presence of halogen at ortho and para positions on the aryl ring in (E)-4-(benzylideneamino)-N-(4,6-dimethylpyrimidin-2-yl)benzenesulfonamide derivatives and hydroxy and halogen in (E)-4-(benzylideneamino)-N-(5-methylisoxazol-3-yl)benzenesulfonamide derivatives increased the urease inhibitory activity. Furthermore, molecular docking studies were carried out in order to investigate the binding mode of this class of compounds to urease. In order to evaluate drug likeness of compounds ADME evaluation was done, and the synthesized compounds were found to be non-toxic and present passive gastrointestinal absorption. The data suggests the synthesized sulphamethazine and sulphamethoxazole derivatives can serve as a novel scaffold to inhibit urease.

Development of sulfonamide-based Schiff bases targeting urease inhibition: Synthesis, characterization, inhibitory activity assessment, molecular docking and ADME studies.

A series of Sulfonamide-based Schiff bases (E)-4-(benzylideneamino)-N-(6-methoxypyridazin-3-yl) benzenesulfonamide (3a-r) targeting Urease Inhibition was synthesized from sulphamethoxy pyridazine and substituted aldehydes. The prepared compounds were characterized by various spectroscopic techniques including FTIR, 1HNMR, 13CNMR, and spectrometric HRMS analysis. The most active agent (3g) bearing halogens and OH groups gave IC50 value of 2.20 µM for urease inhibition against the standard Thiourea (IC50 = 20.03 ± 2.06) and the overall trend within the series was 3g > 3n > 3p > 3j > 3q > 3h, 3o > 3l, 3r > 3k, 3m > 3a > 3d > 3e > 3f. Structure-activity relationship study established that the nature as well as the position of varying groups attached to aryl group had crucial roles in defining the urease inhibition activity. Additionally, in silico investigation was carried out which demonstrated that the compounds exhibit polar and apolar contacts with the crucial residues in the binding site of urease. The ADME analysis suggested all the synthesized compounds to be non-toxic, and likely to undergo passive gastrointestinal absorption. Taken together, the study suggests that the synthesized Sulfonamide-based Schiff bases derivatives may serve as potential hits as urease inhibitors.