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The drugs that are the most useful in all stages of Alzheimer’s disease (AD) are acetylcholinesterase (AChE) inhibitors. The objectives of this work are to generate various QSAR models for such drugs and to select a robust predictive models from the corresponding models. Studies were then focused on finding a range of pyrazole-like AChE inhibitors by 2D and 3D QSAR analysis. The genetic algorithm-based multiple linear regression (GA-MLR) provided the statistically robust 2D QSAR model that depicted the significance of the molecular volume and the number of multiple bonds along with the presence/ absence of specific atom-centred fragments and topological distance between 2D pharmacophoric features. Furthermore, these results were correlated well with the electrostatic and steric contour maps retrieved from the 3D QSAR (i.e., alignment-dependent molecular field analysis). The 2D QSAR analysis developed a highly statistical and reliable model, which was compared with the mechanistic interpretation of 3D structures and their electrostatic and steric field contributions leading to a predictive 3D QSAR model. The molecule- protein interactions, elicited by molecular docking, corroborated with the field interactions, as revealed by 2D QSAR. Thus, the developed computational models and simulation analyses in the current work provide valuable information for the future design of pyrazole and spiropyrazoline analogs, as potent AChE inhibitors.

The present study describes the isolation and structural elucidation of bioactive natural products from the hydro ethanol extract of Dilenia indica L. barks (DIHEEB) and their inhibitory activity against α-amylase and α-glucosidase enzymes. Some natural products including n-nonyl oleate (1), stigmasterol (2), β-sitotenone (3), betulin (4), and betulinic acid (5) were isolated from the DIHEEB extract. These natural products were characterized through IR, NMR, and mass spectroscopy. Among all these compounds, 4 and 5 have shown significant activity to inhibit α-glucosidase and α-amylase, which proves their anti-diabetic effect. The α-amylase and α-glucosidase inhibitory activity of 4 (α-amylase: IC50 68.79±1.6 μg/ml; α-glucosidase: IC50 69.19±1.8 μg/ml;) are very much comparable with known anti-diabetic drug acarbose (IC50 64.70±1.6 μg/ml). But compound 5 also shows a comparable extent of activity against α-amylase and α-glucosidase and it is also well established in the literature. Molecular docking and other in-silico properties were studied to elucidate the interactions and conformations of the isolated molecules with the target protein enzyme. With minimal conformational energy, 4 and 5 bind to the α-amylase (PDB ID: 4GQR) and α-glucosidase (PDB ID: 3A4A) enzymes, as proved by their respective docking score (-8.2 and -9.4 kcal/mol) and having different types of binding interactions. Also, the pharmacokinetics (PK), drug-likeness scores (DLS), and well permeability properties were studied along with no violation of Lipinski's rule. Both in vitro and in silico results suggest that D. indica could be a potential source of anti-diabetic formulations. [ABSTRACT FROM AUTHOR]

A series of new Coumarin hydrazone oxime scaffolds were synthesised as potential anti‐TB agents. The structures of the scaffolds were confirmed by spectroscopic and analytical techniques. X‐ray crystallography confirmed the structure of compound 6‐methyl‐4‐((((Z)‐((E)‐3‐(2‐phenylhydrazono)butan‐2‐ylidene)amino)oxy)methyl)‐2H‐chromen‐2‐one (5a). The coumarin hydrazone oxime scaffolds were tested in‐vitro against the Mycobacterium tuberculosis H37Rv strain, and Vero cells were used to assess cytotoxicity. Compound 5b was obtained as the hit candidate, exhibiting MIC 0.78 μg/mL, showing more potent anti‐TB activity than Rifamycin and comparable activity to Isoniazid. There was minimal cytotoxicity observed against Vero cells for the most active compounds, indicating a good safety‐profile.In addition, the most diligent compound 5b demonstrated substantial binding interactions at the PDB:4DQU enzyme's active site and also displayed greater C‐score value than that of 4DQU ligand which validates the observed results. [ABSTRACT FROM AUTHOR]

Skin aging is a progressive biological process of the human body, and it is not only time-dependent. Differently substituted 3-phenylcoumarins proved to efficiently inhibit tyrosinase. In the current work, new substitution patterns have been explored, and the biological studies were extended to other important enzymes involved in the processes of skin aging, as elastase, collagenase and hyaluronidase. From the studied series, five compounds presented inhibitory activity against tyrosinase, one compound against elastase, eight compounds against collagenase and two compounds against hyaluronidase, being five compounds dual inhibitors. The 3-(4′-Bromophenyl)-5,7-dihydroxycoumarin (1) and 3-(3′-bromophenyl)-5,7-dihydroxycoumarin (2) presented the best profiles against tyrosinase (IC50 = 1.05 µM and 7.03 µM) and collagenase (IC50 = 123.4 µM and 110.4 µM); the 3-(4′-bromophenyl)-6,7-dihydroxycoumarin (4) presented a good inhibition against tyrosinase and hyaluronidase; the 3-(3′-bromophenyl)-6,7-dihydroxycoumarin (5) showed an effective tyrosinase and elastase inhibition; and 6,7-dihydroxy-3-(3′-hydroxyphenyl)coumarin (11) presented a dual profile inhibition against collagenase and hyaluronidase. Furthermore, considering the overall activities tested, compounds 1 and 2 proved to be the most promising anti-aging compounds. These compounds also showed to have a photo-protective effect, without being cytotoxic to human skin keratinocyte cells. To predict the binding site with the target enzymes, computational studies were also carried out. [ABSTRACT FROM AUTHOR]

As a result of the significance of the antifungal activity of thio compounds, the researcher in this study designed and synthesised a novel aniline compound, "2-Hydroxyalkyl dithio aniline" that contained Sulphur-sulphur groups with alkyl moieties. Their goal was to discover potent antifungal and antiviral agents from these compounds. Infrared spectroscopy and elemental analyses both backed up their constructions. Computational chemistry was utilized in the process of developing the product. In this paper, we also discussed computational chemistry and highlighted how it might be useful in the theoretical creation of new compounds. Specifically, author focused on the latter topic. Since the beginning of the 1980s, too develop tiny molecules with great therapeutic promise, computer-aided drug discovery as well as design technologies have proved crucial. Different approaches may be classified as either structure-based or ligand-based. Having knowledge of the target as well as ligand structures is crucial for structure-based techniques, just as it is for high-throughput screening. Methods like as ligand docking, pharmacophore, and ligand design fall under the category of structure-based techniques. In this study, we also explored the mechanism of antimicrobial and antiviral action, which is how it demonstrates its therapeutic potential. [ABSTRACT FROM AUTHOR]

To get an idea about the pharmacokinetics and pharmacodynamics, it is important to study the drug‐protein interaction. Therefore, herein, we studied the interaction of diclofenac sodium (DIC) with human hemoglobin. The binding study of nonsteroidal antiinflammatory drug, DIC with human hemoglobin (HHB) was done by utilizing fluorescence, UV–visible, time‐resolved fluorescence and far‐UV circular dichroism spectroscopy (CD). Various thermodynamic parameters such as enthalpy change (ΔH), entropy change (ΔS), and Gibbs free energy change (ΔG) were also calculated. CD results showed that DIC induces secondary structure change in HHB. Fluorescence resonance energy transfer was also performed. Additionally, it was also observed that DIC inhibits the esterase‐like enzymatic activity of HHB via competitive inhibition. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Series of hydroxylated 2-phenylbenzofuran were synthesized. • Compounds displayed activity against butyrylcholinesterase enzyme. • Importance of number and position of hydroxyl substitution in enzyme activity. • Physicochemical properties of derivatives were characterized. • Docking studies assisted in explaining the structure-activity. Abstract We have designed, synthesized and evaluated a series of hydroxylated 2-phenylbenzofuran derivatives as potential cholinesterase inhibitors. Starting from a series of 2-phenylbenzofurans previously published, in this paper we present a complete synthesis and the influence on the activity of one or two hydroxyl groups located in meta or in meta and para positions respectively of the 2-phenyl ring and highlight the importance of position of hydroxyl groups. Moreover, simultaneous introduction of halogen at position 7 of the benzofuran scaffold resulted in an improved inhibitory activity against the enzyme. To further provide molecular insight and to identify the most probable ligand-binding site of the protein, docking studies were performed for the top-ranked compounds. Docking results revealed conserved ligand-binding residues and supported the role of catalytic site residues in enzyme inhibition. [ABSTRACT FROM AUTHOR]

Abstract: The effect of a potent antimicrobial compound bearing 1,2,3‐triazole core and a tryptophan tail, triazole‐tryptophan hybrid (TTH), with bovine serum albumin (BSA) have been explored using various spectroscopic and molecular docking methods. Studies revealed that TTH strongly quenches the intrinsic fluorophore of BSA by a static quenching mechanism. Time‐resolved fluorescence spectra further confirmed the involvement of static quenching for TTH–BSA system. The calculated thermodynamic parameters; ΔH, ΔS, and ΔG showed that the binding process was spontaneous, exothermic and entropy driven. Synchronous fluorescence, three‐dimensional (3D) fluorescence and circular dichroism data revealed that TTH induces the structural alteration in BSA and enhances its stability. In silico study of TTH–BSA system showed that it binds with BSA at the site I of subdomain IIA. Both the experimental and in silico study showed that the hydrophobic and electrostatic interactions play a major role in TTH–BSA binding. [ABSTRACT FROM AUTHOR]

The understanding of the 3-dimensional enzyme structure is important for the point of protein engineering and applications. Computer-based molecular modelling is a vital tool for theoretical predication of enzyme activities and finding their substrates and inhibitors. SMlipA lipase was cloned from forest soil metagenome and characterized as broad spectrum enzyme with high stability in various organic solvents. In the present study, to understand the mechanism of SMlipA lipase and to identify the key residues involved in enzyme-substrate interaction, three dimensional-computational model of SMlipA has been generated and validated for stereo-chemical and amino-acid environment quality using appropriate programs, and further validation of the active-site architecture was achieved by performing docking studies with different ligand. The three dimensional structure created here provide a new understanding of the ligand preferences and their interaction with protein. [ABSTRACT FROM AUTHOR]

Synthesis, characterization, DNA and protein binding as well as anticancer activity of the organometallic complexes [(η 6 -C 6 H 6 )RuCl(APBI)]Cl ( 1 ), [(η 6 - p -MeC 6 H 4 Pr i )RuCl(APBI)]Cl ( 2 ), [(η 6 -C 6 Me 6 )RuCl(APBI)]Cl ( 3 ), [(η 5 -C 5 Me 5 )RhCl(APBI)]Cl·H 2 O ( 4 ) and [(η 5 -C 5 Me 5 )IrCl(APBI)]Cl·H 2 O ( 5 ) containing 2-aminophenyl benzimidazole (APBI) have been described. The complexes 1 – 5 exhibited strong DNA, protein binding and anticancer activity against cervical cancer (SiHa) cell line. Their binding with calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) have been examined by absorption and emission spectral studies. Strong interactions between complexes and CT-DNA have been affirmed by absorption spectral and EthBr displacement studies, while interaction with BSA via static quenching explored by fluorescence titration, synchronous and 3D fluorescence spectroscopy. The interactions between 1 – 5 and DNA has also been scrutinized by 1 H NMR spectral studies using guanosine as a model for DNA. These results have been supported by DFT calculations and molecular docking studies. Cytotoxicity, apoptosis and in vitro anticancer activity of 1 – 5 toward SiHa cell line have been investigated by MTT assay and acridine (AO)/ethidium bromide (EthBr) fluorescence staining. Overall results revealed that DNA and protein binding, as well as anticancer activity of 1 – 5 follows the order as 5 > 3 > 2 > 1 > 4 . [ABSTRACT FROM AUTHOR]

Background/purpose: Tocopherol from raw pumpkin seeds has been reported to be effective in the alleviation of diabetes through its antioxidant activities. This study evaluates the antidiabetic activities of the tocopherol fraction of raw seeds of Cucurbita pepo L. (CPSE) in a diabetic rat model. In addition, the putative action mechanisms of its botanicals were computationally investigated. Methods: Seed water activity (Aw) was assessed. Tocopherol was extracted and quantified from raw seed oil. The effect of CPSE was studied in poloxamer-407 (PX-407)-induced type 2 diabetic Wistar rats. Glycemic, insulinemic, and lipid profiles, as well as lipid peroxidation status, were evaluated. Glucagon like peptide-1 (GLP-1) content in the cecum was evaluated and histopathological analysis of the pancreas was performed. Further, HYBRID and FRED docking were performed for 10 documented CPSE botanicals, for putative action mechanisms concerning three proteins [protein-tyrosine phosphatase 1B (PTP-1B), peroxisome proliferator-activated receptor gamma (PPAR-γ), and dipeptidyl peptidase IV (DPP-IV)] known to have diabetic therapeutic potential. Results: The Aw of raw seeds was found to be 0.544 ± 0.002. Using tocopherol standards, HPLC determination of CPSE revealed the presence of tocopherol isomers (α, β, γ, and δ). The tocopherol content was found to be 107.4 ± 2.9 mg/100 g of CPSE. When compared to diabetic control (DC) rats, the CPSE-treated diabetic rats presented a significant amelioration of glycemia, insulinemia, and lipid dysmetabolism. A remarkable reduction in oxidative markers and improved cecal and pancreatic characteristics were also observed. Tocopherol isomers have shown a considerable interaction potential with the aforesaid proteins in docking. Conclusion: The results provide pharmacological evidence of CPSE as an antihyperglycemic mediated by the interaction of various botanicals with multiple targets operating in diabetes mellitus (DM). [ABSTRACT FROM AUTHOR]

Antibiotic resistance is one of the main public health concerns of this century. This resistance is also associated with oxidative stress, which could contribute to the selection of resistant bacterial strains. Bearing this in mind, and considering that flavonoid compounds are well known for displaying both activities, we investigated a series of hydroxy-3-arylcoumarins with structural features of flavonoids for their antibacterial activity against different bacterial strains. Active compounds showed selectivity against the studied Gram-positive bacteria compared to Gram-negative bacteria. 5,7-Dihydroxy-3-phenylcoumarin (compound 8) displayed the best antibacterial activity against Staphylococcus aureus and Bacillus cereus with minimum inhibitory concentrations (MICs) of 11 μg/mL, followed by Staphylococcus aureus (MRSA strain) and Listeria monocytogenes with MICs of 22 and 44 μg/mL, respectively. Moreover, molecular docking studies performed on the most active compounds against Staphylococcus aureus tyrosyl-tRNA synthetase and topoisomerase II DNA gyrase revealed the potential binding mode of the ligands to the site of the appropriate targets. Preliminary structure–activity relationship studies showed that the antibacterial activity can be modulated by the presence of the 3-phenyl ring and by the position of the hydroxyl groups at the coumarin scaffold. [ABSTRACT FROM AUTHOR]

Xanthine oxidase (XO) plays a critical role in purine catabolism, catalyzing the conversion of hypoxanthine to xanthine and xanthine to uric acid, contributing to superoxide anion production. This process is implicated in various human diseases, particularly gout. Traditional XO inhibitors, such as allopurinol and febuxostat, while effective, may present side effects. Our study focuses on Asphodelus microcarpus , a plant renowned for traditional anti-inflammatory uses. Recent investigations into its phenolic-rich flowers, notably abundant in luteolin derivatives, reveal its potential as a natural source of XO inhibitors. In the present research, XO inhibition by an ethanolic flowers extract from A. microcarpus is reported. In silico docking studies have highlighted luteolin derivatives as potential XO inhibitors, and molecular dynamics support that luteolin 7- O -glucoside has the highest binding stability compared to other compounds and controls. In vitro studies confirm that luteolin 7- O -glucoside inhibits XO more effectively than the standard inhibitor allopurinol, with an IC 50 value of 4.8 μg/mL compared to 11.5 μg/mL, respectively. These findings underscore the potential therapeutic significance of A. microcarpus in managing conditions related to XO activity. The research contributes valuable insights into the health-promoting properties of A. microcarpus and its potential application in natural medicine, presenting a promising avenue for further exploration in disease management. • A. microcarpus flower extract inhibits xanthine oxidase (XO) via mixed-type inhibition. • Luteolin-7- O -glucoside stably binds XO in AutoDock and 250ns molecular dynamics. • Luteolin 7- O -glucoside demonstrates in vitro XO inhibition (IC 50 4.8 μg/mL). [ABSTRACT FROM AUTHOR]

[Display omitted] • Spectral methods have been used to investigate the interaction of R1 with HHb and BSA. • Thermodynamic parameters suggested exothermic spontaneous binding processes involving hydrogen bonding and van der Waal interaction. • Molecular docking and molecular dynamics have been utilized to discuss the principle binding sites of proteins for R1. • R1 proposes preferentially binding to the hydrophobic cavity in site III of proteins. A Rhodamine-based fluorescent probe R1 has been successfully utilized to detect BSA and HHb proteins via non-covalent bonding. The protein binding nature with R1 has been unravelled by the characteristic changes in absorption, emission and circular dichroism spectra that indicated their noticeable interaction. The experimental results have also shown the moderate strength between proteins and R1 from the quenching of proteins through the static quenching mechanism. The hyperchromism in the absorption band of proteins with R1 has given vital information and binding affinity values have been calculated from Stern-Volmer plots. The calculated values of the thermodynamic parameters revealed a spontaneous binding processes occurring primarily via hydrogen bonding and van der Waal interactions. Furthermore, in-silico approaches have been utilized to make a comparison and conclusion with spectroscopic results. The outcome of these studies could be useful to examine the drug-protein binding for further exploitation. [ABSTRACT FROM AUTHOR]

Snake envenomation leads to the formation of damage–associated molecular patterns (DAMPs), which are mediated by endogenous intracellular molecules. These are recognized by pattern-recognition receptors (PRRs) and can induce sterile inflammation. In the present study, we aim at understanding the mechanisms involved in DAMPs induced sterile inflammation to unravel the novel therapeutic strategies for treating snake bites. The potential of benzodiazepinone derivatives to act against snake venom induced inflammation has been explored in the present investigation. Three compounds VA 17, VA 43 and PA 03 were taken from our library of synthetic compounds. Oxidative stress markers such as lipid peroxidation, superoxide and nitric oxide were measured along with the analysis of DAMPs (IL6, HMGB1, vWF, S100b and HSP70). These compounds have been docked using molecular docking against the snake venom PLA 2 structure (PDB code: 1OXL). The compounds have been found to effectively neutralize viper and cobra venoms induced lethal activity both ex vivo and in vivo. The compounds have also neutralized the viper venom induced hemorrhagic, coagulant, anticoagulant reactions as well as inflammation. The fold of protection have always been found to be higher in case of ex vivo than in in vivo. These compounds have neutralized the venom induced DAMPs as exhibited by IL6, HMGB1, vWF, S100b and HSP70. The fold of neutralization is found to be higher in VA 43. The identified compounds could be used as potential candidates for developing treatment of snakebites in areas where antiserums are not yet available. • Snake envenomation leads to formation of DAMPs. • DAMPs can induce sterile inflammation. • Exploration of potential of benzodiazepinone derivatives against inflammation. • The compounds are characterized to study venom induced pathophysiological changes. • The compounds neutralized the viper and cobra venoms induced lethal activity. [ABSTRACT FROM AUTHOR]

Abstract: This study evaluated the beneficial effects of fructooligosaccharide (FOS) intake from Aureobasidium pullulans using poloxamer-407 (PX-407) induced type 2 diabetes mellitus (T2DM) in rat. Administration of FOS enhanced enzymatic activities of catalase and glutathione reductase in a dose-dependent manner. Significant reduction in fasting plasma triacylglycerol and very low-density lipoprotein level coupled with slight increase in fasting plasma insulin level was observed. Significant decrease in severe glucosuria, proteinuria, blood creatinine, urea and advanced glycation end products was also observed. Supplementation of FOS increased glucagon like peptide-1 content as well as Bifidobacteria and Lactobacilli populations in the caecum. Molecular docking by Gold and Glide software revealed that three sugar types present in the FOS (1-kestose, nystose, and 1-β-fructofuranosyl nystose) are potent dipeptidyl peptidase-IV inhibitors as well as peroxisome proliferator-activated receptor-gamma agonists. This work indicates that FOS can be positioned as a nutraceutical product, beneficial in diabetes-associated metabolic abnormalities. [Copyright &y& Elsevier]

[Display omitted] • A new pyrimidine hybrids was synthesized with the help of WELPSA as an effective catalyst through a multicomponent one-pot Biginelli reaction. • Synthesized compounds were evaluated for α-amylase and α-glucosidase inhibition assays. • All the compounds were found remarkable with excellent IC 50 values than the standard drug acarbose. • DFT calculations were performed using Gaussian 09 software. • Molecular docking study of the synthesized compounds was performed using Auto dock Vina. A green catalyst WELPSA-catalyzed three-component condensation (Biginelli) process involving an aldehyde, barbituric/thiobarbituric/1,3-dimethylbarbituric acid, and urea/thiourea/guanidine hydrochloride in a single pot in presence of a green solvent for the production of DHPM have been presented. The catalyst is reusable and this methodology is scalable. By using the in vitro experiments, the antidiabetic potentiality of synthesized compounds that inhibit α-amylase along with α-glucosidase efficiencies was assessed. All the synthesized compounds except for 4a and 4e , showed the most significant inhibition for α-amylase and α-glucosidase activities. Among the synthesized DHPM compounds, 4c and 4b exhibited significant inhibition profiles compared to the standard antidiabetic drug acarbose. Furthermore, synthesized substances' energy-minimized structures, 3D structures, and DFT calculations were performed using Gaussian 09 software, hybrid models, and MM2 force approaches. Strong hydrogen bonds with amino acid residues Arg-672, Arg-600, Trp-613, Asp-404, Asp-282, and Asp-616 indicate that an α-glucosidase-inhibitory peptide may have hypoglycemic efficacy confirmed by the molecular docking study of the synthesized DHPM. [ABSTRACT FROM AUTHOR]

• New imidazopyridine analogues were designed for anti-TB activity. • I2 and I7 exhibited MIC of 3.12 and 4.16 μg/mL against MTBH 37 Rv strain. • I2 and I7 was found to be more active than standard drug streptomycin. • Molecular docking data were in accordance with the anti-TB results. • Single crystal X-ray and computational photo physical studies were carried out. With the intent to discover new anti-TB compounds, new imidazopyridine analogues were synthesized through Schiff-base reaction. The newly developed imidazopyridines (I1-I8) were characterized using spectroscopic and elemental analysis. In addition the structure of compound I3 was elucidated by the single crystal X-ray diffraction technique. The global chemical reactivity descriptor parameter was calculated using theoretically DFT-B3LYP-6–31G(d) basis set which estimated HOMO-LUMO value and results are discussed. All the newly synthesized compounds were screened for their in vitro anti-tubercular activity, while the most active compounds were subjected to a cytotoxicity assay on Vero cell lines. Most of the tested compounds exhibited significant anti-TB activity with MIC in the range 3.12 – 12.5 μg/mL. Among the synthesized, compound I2 and I7 were found to be more active than the standard anti-TB drug streptomycin and comparable activity to pyrazinamide. A cytotoxicity study on Vero-cell lines confirmed the nontoxic nature of compound I2 and I7 indicating good safety profile. The molecular docking studies on PDB IB: 4ED4 enzyme of Mycobacterium tuberculosis was conducted to investigate mechanisms of anti-TB activity. The compounds displayed excellent hydrogen binding interactions and docking scores against MTB, which were in accordance with the results and further supported its credibility. [Display omitted] [ABSTRACT FROM AUTHOR]

In this study, we have investigated a series of hydroxylated 2-phenylbenzofurans compounds for their inhibitory activity against α -amylase and α -glucosidase activity. Inhibitors of carbohydrate degrading enzymes seem to have an important role as antidiabetic drugs. Diabetes mellitus is a wide-spread metabolic disease characterized by elevated levels of blood glucose. The most common is type 2 diabetes, which can lead to severe complications. Since the aggregates of islet amyloid polypeptide (IAPP) are common in diabetic patients, the effect of compounds to inhibit amyloid fibril formation was also determined. All the compounds assayed showed to be more active against α -glucosidase. Compound 16 showed the lowest IC 50 value of the series, and it is found to be 167 times more active than acarbose, the reference compound. The enzymatic activity assays showed that compound 16 acts as a mixed-type inhibitor of α -glucosidase. Furthermore, compound 16 displayed effective inhibition of IAPP aggregation and it manifested no significant cytotoxicity. To predict the binding of compound 16 to IAPP and α -glucosidase protein complexes, molecular docking studies were performed. Altogether, our results support that the 2-phenylbenzofuran derivatives could represent a promising candidate for developing molecules able to modulate multiple targets involved in diabetes mellitus disorder. Unlabelled Image • Hydroxylated 2-phenylbenzofurans inhibit α -glucosidase. • Compound 16 is 167 times more active than reference compound against α -glucosidase. • Number and position of hydroxyl substitution in enzyme activity were highlighted. • Compound 16 inhibits islet amyloid polypeptide formation. • Physicochemical properties and molecular docking of compound 16 were determined. [ABSTRACT FROM AUTHOR]

CD44 is one of the key cancer stem-like cell (CSC) marker and may have a potential role in tumorigenesis. In this study, we investigated the role of CD44 in prognosis of HNSCC patients, its possible crosstalk with Wnt/β-catenin signaling and modulating cisplatin resistance. We observed increased expression of CD44 in the cut margin of recurrent HNSCC patients were associated with poor prognosis. We observed that inhibition of CD44 by using 1,2,3,4 tetrahydroisoquinoline (THIQ) modulates the expression of Wnt/ β-catenin signaling proteins and further silencing of β-catenin also decreases the expression of CD44. This led us to investigate the possible protein-protein interaction between CD44 and β-catenin. Co-immunoprecipitation study illustrated possible interaction between CD44 and β-catenin which was further confirmed by molecular docking and molecular dynamic (MD) simulation studies. Molecular docking study revealed that one interface amino acid residue Glu642 of β -catenin interacts with Lys92 of CD44 which was also present for 20% of simulation time. Furthermore, we observed that inhibition of CD44 chemosensitizes cisplatin-resistant HNSCC cells towards cisplatin. In conclusion, this study investigated the possible role of CD44 along with Wnt/ β-catenin signaling and their possible therapeutic role to abrogate cisplatin resistance. [ABSTRACT FROM AUTHOR]

Abstract Xanthine oxidase (XO) is an interesting target for the synergic treatment of several diseases. Coumarin scaffold plays an important role in the design of efficient and potent inhibitors. In the current work, twenty 3-arylcoumarins and eight 3-heteroarylcoumarins were evaluated for their ability to inhibit XO. Among all the candidates, 5,7-dihydroxy-3-(3′-hydroxyphenyl)coumarin (compound 20) proved to be the best inhibitor with an IC 50 of 2.13 μM, being 7-fold better than the reference compound, allopurinol (IC 50 = 14.75 μM). To deeply understand the potential of this compound, the inhibition mode was also evaluated. Compound 20 showed an uncompetitive profile of inhibition. Molecular docking studies were carried out to analyze the interaction of compound 20 with the studied enzyme. The binding mode involving residues different from the catalytic site of the binding pocket, is compatible to the observed uncompetitive inhibition. Compound 20 was not cytotoxic at its IC 50 value, as demonstrated by the viability of 99.1% in 3 T3 cells. Furthermore, pharmacokinetics and physicochemical properties were also calculated, which corroborated with the potential of the studied compounds as promising XO inhibitors. [ABSTRACT FROM AUTHOR]

• Novel coumarin-thioether conjugates were synthesised and characterised. • The synthesised compounds are assessed for in vitro anti-TB activity (H 37 Rv strain). • Compound 6b (MIC = 0.39 µg/mL) was twofold more active than Rifampin (0.8 µg/mL). • Compounds 6b and 6f possessed low level of cytotoxicity against Vero cells. • Molecular docking study revealed higher C-score values that supports the findings. In this work, we report a series of 4-(2,6-dimethylphenyl)thio)methyl)-2H-chromen-2-one conjugates as promising leads to treat tuberculosis. Spectroscopic and other analytical methods were used to validate the synthesised compounds. The compounds were assessed for in vitro anti-tubercular activity with the H 37 Rv strain of Mycobacterium tuberculosis. Further, cytotoxicity studies were performed using Vero cells. Most of the synthesised conjugates were effective and displayed notable activity with MIC values in the range 0.39–12.5 µg/mL.The most diligent compound 6b (MIC = 0.39 µg/mL) was twofold more active than standard anti-TB drug Rifampin (0.8 µg/mL) and was comparable to Isoniazid (0.1 µg/mL). Compound 6f also displayed exemplary activity (MIC 0.78 µg/mL). Both compounds 6b and 6f possessed low levels of cytotoxicity, Molecular docking evaluation of the synthesised conjugates and 4DQU ligand demonstrated that the synthesised conjugates had higher C-score values that further supports the obtained results. It indicates compound 6b and 6f are promising lead compounds in search of novel antitubercular drug-like molecules. [Display omitted] [ABSTRACT FROM AUTHOR]

Neisseria gonorrhoeae have progressively developed resistance to almost all antibiotics, and it has become imperative to develop novel approaches to combat its multi-drug resistance. Overexpression of the MtrCDE, an RND family efflux pump, is one of the primary causes of antibiotic resistance in the gonococcus and is considered an important target for combating anti-microbial resistance. PaβN, D13–9001, and other EPIs are identified to target the RND efflux pumps, but due to their cytotoxicity, they have failed in clinical trials. Herein, an extensive pharmacophore-based approach was performed to identify novel EPI inhibitors with improved pharmacology/safety profiles. An integrated computational framework comprising pharmacophore generation, virtual screening using HTVS, SP and XP Glide methodology, MM-GBSA analysis, Induced fit docking, QPLD, DFT, ADMET properties calculation, Molecular Dynamics, and MM-PBSA analysis was performed. The comprehensive study leads to the identification of five non-toxic bioactive compounds, namely - ZINC000008764610, ZINC000030879142, ZINC000030879358, ZINC000253414904, and ZINC000225394671, as potential EPIs for RND efflux pump of Neisseria gonorrhoeae. The five compounds were selected based on the pharmacophore mapping, higher dock score than the known EPIs, binding stability, molecular interactions with the critical residues of MtrD protein, higher ADMET properties, non-toxicity, and free energy estimations. In summary, the analysis led to the identification of five top hits from the natural compound subset of the ZINC database that has a higher binding affinity to the MtrD and adequate physiochemical/pharmacokinetic profile that can be used for the generation of novel EPIs against Neisseria gonorrhoeae. [Display omitted] • Neisseria gonorrheae have shown high multi-drug resistance & needs to be tackled on urgent basis. • Efflux pumps are novel drug targets that can potentiates the use of antibiotics against pathogens. • An extensive pharmacophore based screening was performed to identify novel EPIs for N. gonorrheae. • The lead molecules showed strong binding interactions with the active-site residues of MtrD Ng. • These lead molecules can be used to develop therapeutics for N. gonorrheae caused gonorrhea. [ABSTRACT FROM AUTHOR]

Syntheses and characterizations of the arene ruthenium [(η6-C6H6)RuCl(4-mtdpm)] (1), [(η6-p-MeC6H4Pri)RuCl(4-mtdpm)] (2), and structurally analogous rhodium/iridium complexes [(η5-C5Me5)RhCl(4-mtdpm)] (3) and [(η5-C5Me5)IrCl(4-mtdpm)] (4) [4-mtdpm = 5-(4-methylthiophenyl)dipyrromethene] have been reported. Their identities have been established by satisfactory elemental analyses, electrospray ionization-mass spectrometry (ESI-MS), FT-IR, NMR (¹H, 13C), UV/vis, emission spectral, and electrochemical studies. Structure of the representative complex 3 has been authenticated by X-ray single crystal analyses. The complexes 1-4 effectively bind with calf thymus DNA (CT DNA) through intercalative/electrostatic interactions. In addition, these exhibit significant cytotoxicity toward Dalton lymphoma (DL) cell line and cause static quenching of the bovine serum albumin (BSA) fluorophore. The antiproliferative activity, morphological changes, and apoptosis have been evaluated by MTT assay, acridine orange/ethidium bromide (AO/EtBr) fluorescence staining, and DNA ladder assay. Mode of interaction of the complexes with DNA/protein has also been supported by molecular docking. Various studies revealed remarkable decrease in the in vitro DL cell proliferation and induction of the apoptosis by 1-4, which lies in the order 2 > 1 > 4 > 3. [ABSTRACT FROM AUTHOR]

• Anticancer and anti-TB activity of novel coumarin-azaspiro conjugates (1a-1l). • 1f exhibited the most potent activity against MDA-MB-231cell line (IC 50 = 9.05 µM). • 1g showed most potent activity against A549 cell line (IC 50 = 7.05 µM). • 1c is found to be the hit candidate against MTBH 37 Rv strain with MIC 0.78 µg/mL. In this work, a series of new 8-[(substituted 2-oxo-2H-chromen-4-yl)methyl]-8-azaspiro[4.5]decane-7,9-dione derivatives (1a - 1l) is synthesized and characterized by 1H NMR, 13C NMR, FT-IR, GC-MS and elemental analysis. In addition, the structure of compound 1k has been elucidated using single crystal X-ray diffraction techniques. The synthesized compounds are screened for their anticancer and anti-TB activity. Preliminary anticancer results showed that compounds (1a - 1l) exhibit moderate to potent activity against MDA-MB-231, A549, HT-29 and Hela cancer cell lines. Compound 1f exhibited the most potent activity against MDA-MB-231cell line with IC 50 value of 9.05 µM concentration, compound 1g and 1h showed potent activity against A549 cell line with IC 50 value of 7.05 and 13.31 µM concentration respectively. Compound 1j showed good cytotoxicity against Hela cell line with IC 50 of 16.14 µM, whereas, compound 1l is found to be moderately active against HT-29 cell line with IC 50 of 18.07 µM. Anti-tubercular activity revealed that compound 1c, 1d, 1g, 1h and 1j have significant activity against MTBH 37 Rv strain with MIC 0.78, 1.56, 0.19, 0.39 and 0.78 µg/mL respectively. Further, to investigate the mechanism of anti-TB activity and detailed intermolecular interactions between the synthesized compounds, molecular docking studies are performed. [ABSTRACT FROM AUTHOR]