Therapeutic potential of N4-substituted thiosemicarbazones as new urease inhibitors: Biochemical and in silico approach.

Urease enzyme plays a key role in pathogenesis of gastritis and peptic ulcers. Its inhibition averts our bodies from many disorders including formation of urinary calculi. In agriculture, the high urease content causes severe environmental and hence economic problems. Due to deficiency of effective and safer drugs to tackle the aforementioned disorders, the quest for new scaffolds becomes mandatory in the field of medicinal chemistry. In this regard, we herein report a new series of N4-substituted thiosemicarbazones 3a-v as potential candidates for urease inhibition. These new N4-substituted thiosemicarbazones 3a-v of distant chemical scaffolds were characterized by advanced spectroscopic techniques, such as FTIR, 1HNMR, 13CNMR, ESI-MS and in the case of compound 3g by single crystal X-ray analysis. The compounds were evaluated for their urease inhibitory potential. All newly synthesized compounds showed significant urease inhibitions with IC50 values in range of 2.7 ± 0.320-109.2 ± 3.217 µM. Molecular docking studies were used for interactions pattern and structure-activity relationship for all compounds, which demonstrated excellent binding interactions with the active site residues, such as hydrogen bonding, π-π interactions, π-H and nickel atom coordination.

Synthesis, characterization and molecular docking of some novel hydrazonothiazolines as urease inhibitors.

A series of new hydrazonothiazolines (3a-v) was obtained in good to excellent yields (79-96%) via cyclization of the appropriate thiosemicarbazones with phenacyl bromide. The targeted compounds were characterized by advanced spectroscopic techniques, such as FTIR, 1HNMR, 13CNMR and ESI-MS. The structure of compounds 3n and 3v was unambiguously confirmed by single crystal X-ray analysis. All compounds displayed enhanced inhibitory activity against urease enzyme with IC50 values in range of 1.73 ±â€¯1.57-27.3 ±â€¯0.655 µM when compared to standard thiourea (IC50 = 20.8 ±â€¯0.75 µM). The structure-activity relationship studies demonstrated that the activity of this series is due the central thiazole ring that interacts with nickel atoms in the active site of urease enzyme. Moreover, molecular docking studies were carried out to investigate the binding mode of all active compounds and an inactive (3u) with the active site of the urease enzyme. The docking results are in complete agreement with the experimental finding.

Exploring antidiabetic potential of adamantyl-thiosemicarbazones via aldose reductase (ALR2) inhibition.

The role of aldose reductase (ALR2) in diabetes mellitus is well-established. Our interest in finding ALR2 inhibitors led us to explore the inhibitory potential of new thiosemicarbazones. In this study, we have synthesized adamantyl-thiosemicarbazones and screened them as aldehyde reductase (ALR1) and aldose reductase (ALR2) inhibitors. The compounds bearing phenyl 3a, 2-methylphenyl 3g and 2,6-dimethylphenyl 3m have been identified as most potent ALR2 inhibitors with IC50 values of 3.99 ±â€¯0.38, 3.55 ±â€¯0.26 and 1.37 ±â€¯0.92 µM, respectively, compared with sorbinil (IC50 = 3.14 ±â€¯0.02 µM). The compounds 3a, 3g, and 3m also inhibit ALR1 with IC50 value of 7.75 ±â€¯0.28, 7.26 ±â€¯0.39 and 7.04 ±â€¯2.23 µM, respectively. Molecular docking was also performed for putative binding of potent inhibitors with target enzyme ALR2. The most potent 2,6-dimethylphenyl bearing thiosemicarbazone 3m (IC50 = 1.37 ±â€¯0.92 µM for ALR2) and other two compound 3a and 3g could potentially lead for the development of new therapeutic agents.

Synthesis and characterization of new thiosemicarbazones, as potent urease inhibitors: In vitro and in silico studies.

A new series of N-substituted thiosemicarbazones (3a-u) bearing 2-naphthyl and dihydrobenzofuranyl scaffolds were synthesized in good to excellent yields (78-95%). The synthesized compounds were characterized by advanced spectroscopic techniques, such as FTIR, 1HNMR, 13CNMR and ESI-MS and evaluated as urease inhibitors. The structure of compound 3m was unambiguously confirmed by single crystal X-ray analysis. All compounds showed remarkable activities against urease enzyme with IC50 values in range of 1.4-36.1 µM. The majority of the synthesized compounds showed higher activity than the standard compound thiourea. Molecular docking was performed to study the mode of interaction of these compounds and their structure-activity relationship. These studies revealed that the compounds bind at the active site and interacts with the nickel atom present in the binding site. The molecular docking demonstrated excellent co-relations with the experimental findings.

Benzoxazinone-thiosemicarbazones as antidiabetic leads via aldose reductase inhibition: Synthesis, biological screening and molecular docking study.

Aldose reductase is an important enzyme in the polyol pathway, where glucose is converted to fructose, and sorbitol is released. Aldose reductase activity increases in diabetes as the glucose levels increase, resulting in increased sorbitol production. Sorbitol, being less cell permeable tends to accumulate in tissues such as eye lenses, peripheral nerves and glomerulus that are not insulin sensitive. This excessive build-up of sorbitol is responsible for diabetes associated complications such as retinopathy and neuropathy. In continuation of our interest to design and discover potent inhibitors of aldo-keto reductases (AKRs; aldehyde reductase ALR1 or AKR1A, and aldose reductase ALR2 or AKR1B), herein we designed and investigated a series of new benzoxazinone-thiosemicarbazones (3a-r) as ALR2 and ALR1 inhibitors. Most compounds exhibited excellent inhibitory activities with IC50 values in lower micro-molar range. Compounds 3b and 3l were found to be most active ALR2 inhibitors with IC50 values of 0.52 ±â€¯0.04 and 0.19 ±â€¯0.03 µM, respectively, both compounds were more effective inhibitors as compared to the standard ALR2 inhibitor (sorbinil, with IC50 value of 3.14 ±â€¯0.02 µM).

Improved physicochemical characteristics of artemisinin using succinic acid.

Artemisinin (ARMN) is a potent antimalarial drug, which is effective against multidrug resistant strains of Plasmodium falciparum and produces rapid recovery even in patients with cerebral malaria. Being poorly soluble in water, artemisinin is incompletely absorbed after oral intake due to poor dissolution characteristics in the intestinal fluids. To enhance these properties, solid dispersions of artemisinin with succinic acid (SUC) were prepared using drug-carrier ratios 1 : 1, 1 : 4, 1 : 6, 1 : 8 and 1 : 10 by solvent evaporation and freeze drying methods. These solid dispersions were characterized by differential scanning calorimetery (DSC), Fourier transform infrared spectroscopy (FTIR), x-ray diffraction patterns (XRD), phase solubility and dissolution kinetics evaluated by applying zero order, first order, Higuchi, and Korsmeyer-Peppas models. Physical mixtures produced significantly higher aqueous solubility and rate of dissolution as compared to artemisinin alone. The dissolution profiles of all formulations followed Higuchi model and exhibited diffusion-controlled release of drug. Solvent evaporation method (SLVPs) exhibited improved solubility and freeze dried solid dispersions (FDSDs) produced highest solubility but stability constant was opposite. ARMN and SUC both were found completely crystalline as shown by their XRD patterns. Physical mixtures (PMs) showed reduced intensity in their XRD patterns while solid dispersions by SLVPs exhibited twice reduced intensity and much displaced angles, whereas FDSDs showed synergistic effects in some of ARMN and SUC peaks. DSC thermograms of FDSDs at drug-carrier ratios 1 : 1-1 : 4 showed lower melting temperature and enthalpy change (deltaH) values than respective SLVPs, whereas at higher ratios, a reverse was true. SLVPs showed displaced methyl stretching bands at lower drug-carrier ratios and exhibited O-H stretching characteristic bands of SUC at higher drug-carrier ratios. In addition, carbonyl group and C-O stretching vibrations characteristic of SUC (1307 cm(-1)) appeared prominently compared to PMs, whereas C-O stretching characteristic bands of ARMN disappeared at higher ratios. FDSDs exhibited distinct nature of bonding compared to respective SLVPs and PMs.

Improved physicochemical characteristics of artemisinin-nicotinamide solid dispersions by solvent evaporation and freeze dried methods.

Artemisinin (ARMN) is a drug of choice against drug-resistant malaria especially due to Plasmodium falciparum. Being poorly soluble in water, its solid dispersions with nicotinamide (NA) were prepared at various drug-carrier ratios (1:1, 1:4, 1:6, 1:8, 1:10) by solvent evaporation and freeze drying methods. These solid dispersions were characterized by differential scanning calorimetery (DSC), fourier transform infrared spectroscopy (FTIR), X-ray diffraction patterns (XRD), phase solubility and dissolution studies. Artemisinin and nicotinamide both were found completely crystalline as shown by their XRD patterns. Physical mixtures (PMs) showed decreased intensity in their XRD patterns while solid dispersions by solvent evaporation method (SLVPs) exhibited displaced angles and decreased intensity whereas freeze dried solid dispersions (FDSDs) showed least number of peaks having low intensity and maximum displaced angles. DSC thermograms of drug-carrier ratios at 1:1-1:4 showed lower melting temperature than artemisinin and nicotinamide in all preparations. Endothermic temperature of artemisinin in PMs and SLVPs increased with rise of nicotinamide content upto 1:6 ratio followed by decline. All samples showed crystallization temperature below the artemisinin except drug-carrier ratio 1:6 of PMs while δH value was minimum at this ratio. FDSDs produced lowest endothermic temperature than corresponding PMs and SLVPs. SLVPs exhibited band shifting in both functional and fingerprint region compared to respective PMs as exhibited by their FTIR spectra. FDSDs and SLVPs showed different nature of bonding among artemisinin and nicotinamide. FDSDs produced strongest CONH(2) bonding followed by SLVPs and PMs respectively. PMs produced significantly higher aqueous solubility and rate of dissolution as compared to artemisinin alone. SLVPs exhibited improved solubility and dissolution profile corresponding to PMs. FDSDs showed highest release rate and aqueous solubility followed by SLVPs and PMs at all ratios. PMs and SLVPs showed their highest dissolution profile at 1:6 drug-carrier ratio followed by gradual decrease while FDSDs progressed in dissolution rate with increase of nicotinamide content successively upto maximum at 1:10 ratio.

Tuning of diphenylamine subphthalocyanine based small molecules with efficient photovoltaic parameters for organic solar cells.

In this theoretical research, four donor molecules with diphenylamine subphthalocyanine (SubPc) as a common core, flanked with various electron-withdrawing groups at the central position containing Methyl-2-cyanoacrylate in C1, 3-methyl-5-methylene-2-thioxothiazolidin-4-one in C2, 2-(2-methylene-1-oxo-1H-inden-3(2H)-ylidene) malononitrile in C3, and Methyl-2-(5-methylene-4-oxo-2-thioxothiazoliden-3-yl) acetate in C4, have been designed. To analyze photovoltaic applications of all the studied molecules (C1-C4), quantum chemical simulations i.e., absorption profiles, frontier molecular orbitals (FMOs), the density of states (DOS), transition density matrix, and open-circuit voltage, have been performed availing DFT and TD-DFT approach with selected B3LYP functional /6-31G (d,p) level of theory. Among all the substituted molecules, C3 revealed highest molar absorption coefficient (601 nm), efficient electron density transfer in FMOs, and lowest energy band gap (1.70 eV) owing to the elongated conjugation along with the compelling electron-withdrawing nature of its axial acceptor moiety. All investigated molecules showed profound peaks in the visible region of the absorption spectrum as well as had low electron and hole mobilities in contrast to that of the reference (R) molecule. The observed binding energies (in electron-volt) of C2 (0.67), C3 (0.10), and C4 (0.47) molecules are found to be lower than R. Hence, these findings reveal that all designed candidates (C1-C4) could be effective and favorable applicants to enhance the energy efficiency of small molecule (SM) based organic solar cells (OSCs).

Development and exploration of novel substituted thiosemicarbazones as inhibitors of aldose reductase via in vitro analysis and computational study.

The role of aldose reductase (ALR2) in causing diabetic complications is well-studied, with overactivity of ALR2 in the hyperglycemic state leading to an accumulation of intracellular sorbitol, depletion of cytoplasmic NADPH and oxidative stress and causing a variety of different conditions including retinopathy, nephropathy, neuropathy and cardiovascular disorders. While previous efforts have sought to develop inhibitors of this enzyme in order to combat diabetic complications, non-selective inhibition of both ALR2 and the homologous enzyme aldehyde reductase (ALR1) has led to poor toxicity profiles, with no drugs targeting ALR2 currently approved for therapeutic use in the Western world. In the current study, we have synthesized a series of N-substituted thiosemicarbazones with added phenolic moieties, of which compound 3m displayed strong and selective ALR2 inhibitory activity in vitro (IC50 1.18 µM) as well as promising antioxidant activity (75.95% free radical scavenging activity). The target binding modes of 3m were studied via molecular docking studies and stable interactions with ALR2 were inferred through molecular dynamics simulations. We thus report the N-substituted thiosemicarbazones as promising drug candidates for selective inhibition of ALR2 and possible treatment of diabetic complications.

Development, Molecular Docking, and In Silico ADME Evaluation of Selective ALR2 Inhibitors for the Treatment of Diabetic Complications via Suppression of the Polyol Pathway.

Diabetic complications are associated with overexpression of aldose reductase, an enzyme that catalyzes the first step of the polyol pathway. Osmotic stress in the hyperglycemic state is linked with the intracellular accumulation of sorbitol along with the depletion of NADPH and eventually leads to oxidative stress via formation of reactive oxygen species and advanced glycation end products (AGEs). These kinds of mechanisms cause the development of various diabetic complications including neuropathy, nephropathy, retinopathy, and atherosclerotic plaque formation. Various aldose reductase inhibitors have been developed to date for the treatment of diabetic complications, but all have failed in different stages of clinical trials due to toxicity and poor pharmacokinetic profiles. This toxicity is rooted in a nonselective inhibition of both ALR2 and ALR1, homologous enzymes involved in the metabolism of toxic aldehydes such as methylglyoxal and 3-oxyglucosazone. In the present study, we developed a series of thiosemicarbazone derivatives as selective inhibitors of ALR2 with both antioxidant and antiglycation potential. Among the synthesized compounds, 3c exhibited strong and selective inhibition of ALR2 (IC50 1.42 µM) along with good antioxidant and antiglycative properties. The binding mode of 3c was assessed through molecular docking and cluster analysis via MD simulations, while in silico ADME evaluation studies predicted the compounds' druglike properties. Therefore, we report 3c as a drug candidate with promising antioxidant and antiglycative properties that may be useful for the treatment of diabetic complications through selective inhibition of ALR2.

Inhibitory Efficacy of Thiosemicarbazones for Carbonic Anhydrase II (Bovine and Human) as a Target of Calcification and Tumorigenicity.

BACKGROUND: Carbonic anhydrase II (CA-II) is associated with calcification, tumorigenicity, epilepsy, osteoporosis, and several other physiological or pathological processes. CA-II inhibitors can be used to reduce the intraocular pressure usually associated with glaucoma. OBJECTIVE: In search for potent CA-II inhibitors, a series of thiosemicarbazone derivatives (3a-u) was synthesized. METHODS: This series was evaluated against bovine and human carbonic anhydrase II (bCA-II and hCA-II) and their docking studies were carried out. RESULTS: In the preliminary screening, most of the compounds exhibited significant inhibition of bCA-II and hCA-II. The predictive structure-activity relationship suggested that the thiosemicarbazide moiety plays a key role in the inhibition of enzyme activity and substitution at R position and has a remarkable contribution to the overall activity. The kinetic studies of the most active inhibitors of bCA-II (3d, 3e, 3l, 3f, and 3p) and hCA-II (3g) were performed against bCA-II and hCA-II, respectively to investigate their mode of inhibition and dissociation constants (Ki). CONCLUSION: Subsequently, (3e, 3f, 3l and 3p) were identified as competitive inhibitors of bCA-II with Ki values of 5.02-14.70 µM, while (3d) as a noncompetitive inhibitor of bCA-II (Ki = 2.5 ± 0.015 µM), however, (3g) demonstrated competitive inhibition of hCA-II with a Ki value of 5.95 ± 0.002 µM. The selectivity index reflects that compound (3g) is more selective for hCA-II. The binding modes of these compounds with bCA-II and hCA-II were investigated by structure-based molecular docking, and the docking results are in complete agreement with the experimental findings.

Synthesis of indole-substituted thiosemicarbazones as an aldose reductase inhibitor: an in vitro, selectivity and in silico study.

Aim: Indole is an important component of many drug molecules, and its conjugation with thiosemicarbazone moiety would be advantageous in finding lead compounds for the development of diabetic complications. Methodology: We have designed, synthesized and evaluated a series of 17 indole-thiosemicarbazones (3a-q) as aldose reductase (ALR2) and aldehyde reductase (ALR1) inhibitors. Results: After in vitro evaluation, all indole-thiosemicarbazones showed significant inhibition against both enzyme ALR1 and ALR2 with IC50 in range of 0.42-20.7 and 1.02-19.1 µM, respectively. The docking study was also carried out to consider the putative binding of molecules with the target enzymes. Conclusion: Compound 3f was found to be most active and selective for ALR2. The indole-thiosemicarbazones series described here has selective hits for diabetes-mellitus-associated complications.

Exploring synthetic and therapeutic prospects of new thiazoline derivatives as aldose reductase (ALR2) inhibitors.

Inhibition of aldose reductase (ALR2) by using small heterocyclic compounds provides a viable approach for the development of new antidiabetic agents. With our ongoing interest towards aldose reductase (ALR2) inhibition, we have synthesized and screened a series of thiazoline derivatives (5a-k, 6a-f, 7a-1 & 8a-j) to find a lead as a potential new antidiabetic agent. The bioactivity results showed the thiazoline-based compound 7b having a benzyl substituent and nitrophenyl substituent-bearing compound 8e were identified as the most potent molecules with IC50 values of 1.39 ± 2.21 µM and 1.52 ± 0.78 µM respectively compared with the reference sorbinil with an IC50 value of 3.14 ± 0.02 µM. Compound 7b with only 23.4% inhibition for ALR1 showed excellent selectivity for the targeted ALR2 to act as a potential lead for the development of new therapeutic agents for diabetic complications.