Structural basis for the binding of famotidine, cimetidine, guanidine, and pimagedine with serine protease.

Serine proteases are among the important groups of enzymes having significant roles in cell biology. Trypsin is a representative member of the serine superfamily of enzymes, produced by acinar cells of pancreas. It is a validated drug target for various ailments including pancreatitis and colorectal cancer. Premature activation of trypsin is involved in the lysis of pancreatic tissues, which causes pancreatitis. It is also reported to be involved in colorectal carcinoma by activating other proteases, such as matrix metalloproteinase (MMPs). The development of novel trypsin inhibitors with good pharmacokinetic properties could play important roles in pharmaceutical sciences. This study reports the crystal structures of bovine pancreatic trypsin with four molecules; cimetidine, famotidine, pimagedine, and guanidine. These compounds possess binding affinity towards the active site (S1) of trypsin. The structures of all four complexes provided insight of the binding of four different ligands, as well as the dynamics of the active site towards the bind with different size ligands. This study might be helpful in designing of new potent inhibitors of trypsin and trypsin like serine proteases.

Identification, crystallization, and first X-ray structure analyses of phenyl boronic acid-based inhibitors of human carbonic anhydrase-II.

Human carbonic anhydrases (hCAs) play a central role in various physiological processes in the human body. HCAs catalyze the reversible hydration of CO2 into HCO3-, and hence maintains the fluid and pH balance. Overexpression of CA II is associated with diseases, such as glaucoma, and epilepsy. Therefore, CAs are important clinical targets and inhibition of different isoforms, especially hCA II is used in treatment of glaucoma, altitude sickness, and epilepsy. Therapeutically used CA inhibitors (CAI) are sulfonamide-based, such as acetazolamide, dichlorphenamide, methazolamide, ethoxzolamide, etc. However, they exhibit several undesirable effects such as numbness, tingling of extremities, malaise, metallic taste, fatigue, renal calculi, and metabolic acidosis. Therefore, there is an urgent need to identify safe and effective inhibitors of the hCAs. In this study, different phenyl boronic acids 1-5 were evaluated against bovine (bCA II) and hCA II. Among all, compound 1 (4-acetylphenyl boronic acid) was found to be active against bCAII and hCA II with IC50 values of 246 ± 0.48 and 281.40 ± 2.8 µM, respectively, while the remaining compounds were found in-active. Compound 1 was identified as competitive inhibitor of hCA II enzyme (Ki = 283.7 ± 0.002 µM). Additionally, compound 1 was found to be non-toxic against BJ Human fibroblast cell line. The X-ray crystal structure for hCA II in-complex with compound 1 was evaluated to a resolution of 2.6 Å. In fact, this the first structural analysis of a phenyl boron-based inhibitor bound to hCA II, allowing an additional structure-activity analysis of the compounds. Compound 1 was found to be directly bound in the active site of hCA II by interacting with His94, His119, and Thr199 residues. In addition, a bond of 3.11 Å between the zinc ion and coordinated boron atom of the boronic acid moiety of compound 1 was also observed, contributing to binding affinity of compound 1 for hCA II. PDB ID: 8IGF.

Isolation of secondary metabolites from Syzygium aromaticum (L.) Merr. & L.M.Perry. (cloves), and evaluation of their biological activities.

Phytochemical investigation of dried flower buds of Syzygium aromaticum (L.) Merr. & L.M.Perry. (clove) led to the isolation and identification of fourteen known compounds, oleanolic acid (1), betulinic acid (2), para methyl benzoic acid (3), sabrinic acid (4) eucalyptolic acid (5), nigricin (6), 3-O-trans-para-coumaroylmaslinic acid (7), methyl maslinate (8), maslinic acid (9), 3, 4, 5-trimethoxy-3',4'-O,O-methylideneflavellagic acid (10), lantanone (11) 3,4,3'-trimethoxyellagic acid (12), 11-oxo-oleanolic acid (13), and ß-sitosterol-3-O-ß-D-glucopyranoside (14). Their structures were identified by 1H NMR, 13C NMR, Mass spectroscopic techniques, and comparison with the literature data. Compounds 3, and 7-9 showed a strong mortality against root knot nematode, Meloidogyne incognita at 0.125% concentration after 72 hours (88-92% inhibition). Compound 4 showed a good anti-glycation activity with IC50 = 142.0 ± 1.8 µM when compared with standard, i.e. rutin (IC50 = 54.59 ± 2.20 µM). Compound 10 showed a comparable urease inhibitory activity (IC50 = 26.1 ± 0.19 µM) with the positive control thiourea (IC50 = 24.5 ± 0.34 µM).

Anti-glycation properties of Illicium verum Hook. f. fruit in-vitro and in a diabetic rat model.

BACKGROUND: Chronic hyperglycemic triggers the non-enzymatic glycation of biomolecules, resulting in the production of advanced glycation endproducts, that lead to several micro- and macrovascular complications. Therefore, the discovery of new, effective, and safe anti-glycation agents is an important need. One of the best choices for the management of diabetes is to use complementary and alternative medicinal therapies. Therefore, the present study was designed to evaluate the anti-glycation activity of ethanolic extract of Illicium verum Hook. f. (Star anise, a frequently used spice and medicinally important herb). METHODS: The anti-glycation activity of ethanolic extract of Illicium verum Hook. f. was determined by using both in-vitro and in-vivo assays. HSA-fructose glycation model was employed to assess the in-vitro inhibition of protein glycation, additionally cross-linked AGEs (formed by incubating lysozyme with fructose) were assessed by SDS polyacrylamide gel electrophoresis. Dual inhibitory mechanisms, i.e., antioxidant and metal chelating activities, were also evaluated by using DPPH, ABTS, and Fe (II)-chelation assays. Acute toxicity of I. verum extract was also performed (by administrating different doses i.e. 2,000, 1,500, 1,000, and 500 mg/kg of body weight). Finally, in-vivo anti-glycation potential was evaluated by 7 weeks of administration of I. verum extract in streptozotocin-induced diabetic rats. RESULTS: In HSA-fructose glycation model, extract of I. verum showed a good inhibitory activity with IC50 value of 0.11±0.001 mg/mL, as compared to the standard inhibitor, rutin (IC50 = 0.02±0.01 mg/mL). Extract of I. verum showed inhibitory activity in DPPH, and ABTS radical scavenging assays with IC50 values of 130±1.0, and 57±2.0 µg/mL, respectively, while it was found to be inactive in the Fe+2-chelation assay. The extract was found to be non-toxic, and reduce the elevated blood glucose, urea, lipid, liver function parameters, and renal AGEs levels in streptozotocin-induced diabetic rats. CONCLUSIONS: These results suggest that I. verum supplementation might help to reduce the burden of AGEs, and may have potential in preventing diabetes-associated complications.

New isolate from Salvinia molesta with antioxidant and urease inhibitory activity.

Urease plays a significant role in the pathogenesis of urolithiasis pyelonephritis, urinary catheter encrustation, hepatic coma, hepatic encephalopathy, and peptic acid duodenal ulcers. Salvinia molesta was explored to identify new bioactive compounds with particular emphasis on urease inhibitors. The aqueous methanol extract was fractionated using solvents of increasing polarity. A series of column chromatography and later HPLC were performed on butanol extract. The structures of the resulting pure compounds were resolved using NMR (1D and 2D), infrared, and mass spectroscopy. The novel isolate was evaluated for antioxidant activity (using DPPH, superoxide anion radical scavenging, oxidative burst, and Fe+2 chelation assays), anti-glycation behavior, anticancer activity, carbonic anhydrase inhibition, phosphodiesterase inhibition, and urease inhibition. One new glucopyranose derivative 6'-O-(3,4-dihydroxybenzoyl)-4'-O-(4-hydroxybenzoyl)-α/ß-D-glucopyranoside (1) and four known glycosides were identified. Glycoside 1 demonstrated promising antioxidant potential with IC50 values of 48.2 ± 0.3, 60.3 ± 0.6, and 42.1 ± 1.8 µM against DPPH, superoxide radical, and oxidative burst, respectively. Its IC50 in the Jack bean urease inhibition assay was 99.1 ± 0.8 µM. The mechanism-based kinetic studies presented that compound 1 is a mixed-type inhibitor of urease with a Ki value of 91.8 ± 0.1 µM. Finally, molecular dynamic simulations exploring the binding mode of compound 1 with urease provided quantitative agreement between estimated binding free energies and the experimental results. The studies corroborate the use of compound 1 as a lead for QSAR studies as an antioxidant and urease inhibitor. Moreover, it needs to be further evaluated through the animal model, that is, in vivo or tissue culture-based ex-vivo studies, to establish their therapeutic potential against oxidative stress phosphodiesterase-II and urease-induced pathologies.

In vitro antiglycation and antioxidant properties of benzophenone thiosemicarbazones.

Fifteen benzophenone thiosemicarbazones were synthesized and their in vitro antiglycation activity was evaluated. The most active compound 2 (IC50 = 118.15±2.41µM) showed two folds potent activity than the standard, rutin (IC50 = 294.5±1.5µM). Compounds 1 and 3-7 showed good to moderate antiglycation activity in the range of 204.14 - 488.54µM. These compounds were also evaluated for antioxidant activity. Their structure-activity relationships have been developed. The results reveal the potential of these compounds as leads for further studies towards the development of antidiabetic drugs.

Isolation of Antidiabetic Withanolides from Withania coagulans Dunal and Their In Vitro and In Silico Validation.

Withania coagulans (W. coagulans) is well-known in herbal medicinal systems for its high biological potential. Different parts of the plant are used against insomnia, liver complications, asthma, and biliousness, as well as it is reported to be sedative, emetic, diuretic, antidiabetic antimicrobial, anti-inflammatory, antitumor, hepatoprotective, antihyperglycemic, cardiovascular, immuno-suppressive and central nervous system depressant. Withanolides present in W. coagulans have attracted an immense interest in the scientific field due to their diverse therapeutic applications. The current study deals with chemical and biological evaluation of chloroform, and n-butanol fractions of W. coagulans. The activity-guided fractionation of both extracts via multiple chromatographic steps and structure elucidation of pure isolates using spectroscopies (NMR, mass spectrometry, FTIR and UV-Vis) led to the identification of a new withanolide glycoside, withacogulanoside-B (1) from n-butanol extract and five known withanolides from chloroform extract [withanolid J (2), coagulin E (3), withaperuvin C (4), 27-hydroxywithanolide I (5), and ajugin E (6)]. Among the tested compounds, compound 5 was the most potent α-glucosidase inhibitor with IC50 = 66.7 ± 3.6 µM, followed by compound 4 (IC50: 407 ± 4.5 µM) and compound 2 (IC50: 683 ± 0.94 µM), while no antiglycation activity was observed with the six isolated compounds. Molecular docking was used to predict the binding potential and binding site interactions of these compounds as α-glucosidase inhibitors. Consequently, this study provides basis to discover specific antidiabetic compounds from W. coagulans.

Anti-glycating and anti-oxidant compounds from traditionally used anti-diabetic plant Geigeria alata(DC) Oliv. & Hiern.

A new sesquiterpene lactone geigerianoloide (1) and four known flavonoids axillarin (2), quercetin (3), 3-methoxy-5,7,3',4'-tetrahydroxy-flavone (4) and hispidulin (5) were isolated from Geigeria alata (DC) Oliv. & Hiern. (Asteraceae). Structures were deduced using 1H- and 13C- NMR spectroscopy, mass spectrometry, while the structure of compound 1 was also deduced using X-ray crystallography technique.Geigeria alata is traditionally used for diabetes, therefore compounds were tested for anti-glycation activity, in which compounds 2 and 3 showed potent activities (IC50 values of 246.97 ± 0.83 and 262.37 ± 0.22 µM, respectively) compared to IC50 value 294.50 ± 1.5 µM of rutin. Moreover, compound 4 exhibited a comparable activity to rutin (IC50 = 293.28 ± 1.34 µM). Compound 5 showed a weak activity.Compounds 2, 3, and 4 exhibited potent DPPH radical scavenging activity (IC50 = 0.1 ± 0.00, 0.13 ± 0.00 and 0.15 ± 0.01 µM, respectively). Compounds 2, 3, and 4 demonstrated significant superoxide anion scavenging activity with IC50 values of 0.14 ± 0.001, 0.17 ± 0.00, and 0.11 ± 0.006 µM, respectively.

Crystal Structure of Mistletoe Lectin I (ML-I) from Viscum album in Complex with 4-N-Furfurylcytosine at 2.85 Å Resolution.

BACKGROUND: Viscum album (the European mistletoe) is a semi-parasitic plant, which is of high medical interest. It is widely found in Europe, Asia, and North America. It contains at least three distinct lectins (i.e. ML-I, II, and III), varying in molecular mass and specificity. Among them, ML-I is in focus of medical research for various activities, including anti-cancer activities. To understand the molecular basis for such medical applications, a few studies have already addressed the structural and functional analysis of ML-I in complex with ligands. In continuation of these efforts, we are reporting the crystal structure of ML from Viscum album in complex with the nucleic acid oxidation product 4-N-furfurylcytosine (FC) refined to 2.85 Å resolution. FC is known to be involved in different metabolic pathways related to oxidative stress and DNA modification. METHODS: X-ray suitable hexagonal crystals of the ML-I/FC complex were grown within four days at 294 K using the hanging drop vapor diffusion method. Diffraction data were collected up to a resolution of 2.85 Å. The ligand affinity was verified by in-silico docking. RESULTS: The high-resolution structure was refined subsequently to analyze particularly the active site conformation and a binding epitope of 4-N-furfurylcytosine. A distinct 2Fo-Fc electron density at the active site was interpreted as a single FC molecule. The specific binding of FC is achieved also through hydrophobic interactions involving Tyr76A, Tyr115A, Glu165A, and Leu157A of the ML-I A-chain. The binding energy of FC to the active site of ML-I was calculated as well to be -6.03 kcal mol-1. CONCLUSION: In comparison to other reported ML-I complexes, we observed distinct differences in the vicinity of the nucleic acid base binding site upon interaction with FC. Therefore, data obtained will provide new insights in understanding the specificity, inhibition, and cytotoxicity of the ML-I A-chain, and related RIPs.

Drug repurposing: In-vitro anti-glycation properties of 18 common drugs.

Drug repositioning or repurposing, i.e. identifying new indications for existing drugs, has gained increasing attention in the recent years. This approach enables the scientists to discover "new targets" for known drugs in a cost and time efficient manner. Glycation, the non-enzymatic reaction of sugars with proteins or nucleic acids to form early glycation (Amadori or fructosamine) products, is a key molecular basis of diabetic complications. Inhibiting the process of non-enzymatic protein glycation is one of the key strategies to prevent glycation-mediated diabetic complications. The present study focuses on the anti-glycation activity of 18 drugs, commonly used for the treatment of gastrointestinal, central nervous system, inflammatory diseases, bacterial infections, and gout. This study was carried out by using two in-vitro protein anti-glycation assay models. Results revealed that nimesulide (3), a non-steroidal anti-inflammatory drug, possesses a good anti-glycation activity in in-vitro BSA-MG and BSA-glucose glycation models with IC50 values of 330.56 ± 2.90, and 145.46 ± 16.35 µM, respectively. Phloroglucinol dihydrate (11), a drug used for the treatment of gastrointestinal diseases, showed a weak activity in BSA-MG glycation model (IC50 = 654.89 ± 2.50 µM), while it showed a good activity in BSA-glucose assay (IC50 = 148.23 ± 0.15 µM). Trimethylphloroglucinol (9), a drug used for the treatment of pain related to functional disorders of the digestive and biliary tracts, also showed a good antiglycation activity in BSA-MG model (IC50 = 321.15 ± 1.26 µM), while it was found to be inactive in in-vitro BSA-glucose assay (IC50 = 12.95% inhibition). These activities of drugs were compared with the anti-glycation activity of the standard, rutin (IC50 = 294.5 ± 1.50 µM in BSA-MG glycation model, and IC50 = 86.94 ± 0.24 µM in BSA- glucose model). Rest of the drugs exhibited a relatively weak antiglycation activity. This study identifies nimesulide (3), and phloroglucinol dihydrate (11) as new inhibitors of in-vitro protein glycation for further investigations as potential anti-diabetic agents.

Bioactive chemical constituents of Duboscia macrocarpa Bocq., and X-ray diffraction study of 11ß, 12ß-epoxyfriedours-14-en-3α-ol.

A new γ-lactone triterpenoid, Evodoulolide (1) and a new triterpenoid Duboscic acid B (2), along with five known compounds, maslinic acid (3), arboreic acid (4), (E)-3-(4-hydroxyphenyl)-N-[2-(4-hydroxyphenyl) ethyl] prop-2-enamide (5), (E)-heptacos-19-enoic acid (6) and 11ß,12ß-epoxyfriedours-14-en-3α-ol (7) were isolated from the trunk wood of Duboscia macrocarpa. Their structures were elucidated from extensive 1D- and 2D-NMR and MS and by comparison of their spectra with published data. Compounds 1, 3, 5 and 6 exhibited significant α-glucosidase inhibitory activity. Compound 5 was found to be a potent inhibitor (IC50=5.1±0.1µM) of α-glucosidase as compared to acarbose (IC50=625.0±1µM) used as standard drug. These compounds did not show anti-glycation activity using the BSA-MG glycation model or inhibition against the α-chymotrypsin enzyme. The chemotaxonomic connotation of the isolated secondary metabolites is also herein described. The single-crystal X-ray and absolute configuration diffraction analysis of 11α, 12α-epoxyfriedours-14-en-3-ol (7) is also described here for the first time.

In-Vitro dual inhibition of protein glycation, and oxidation by some Arabian plants.

BACKGROUND: Diabetes mellitus is a metabolic disorder of epidemic proportion, projected to become the major cause of morbidity and mortality in the world in future. Despite extensive research in understanding this disease at molecular level, and the discovery of new drugs, diabetes and its complications remain largely untreated. Many of the late diabetic complications are associated with the glycation of proteins in the body. Natural flora has long been a rich source for therapeutic agents, especially against diabetes. The present study deals with the anti-glycation properties of some medicinally important plants of Arabian region. METHODS: Twenty-six medicinal plants, commonly found in different regions of Arabian Peninsula, were evaluated for their protein anti-glycation activity by using BSA-MG glycation assay in-vitro. The extracts were incubated with BSA and MG at 37 °C for 9 days, each sample was then examined for the presence of fluorescence (λex 330 nm, and λem 420 nm), which represent the extent of protein glycation. Antioxidant activity was evaluated by using 1,1-diphenyl- 2-picrylhydrazyl (DPPH), iron chelation, and superoxide radical scavenging asaays. RESULTS: The data revealed that out of 26 medicinal plants, five plants viz. Sida cordifolia, Plumbago zeylanica, Tribulus terrestris, Glycyrrhiza glabra, and Rosa indica were active against the in-vitro protein glycation with IC50 values between 0.408- 1.690 mg/mL. Among the active plants, Glycyrrhiza glabra L. was found to be the most potent (IC50 = 0.408 ± 0.027 mg/mL), followed by Rosa indica (IC50 = 0.596 ± 0.0179 mg/mL), and Sida cordifolia L. (IC50 = 0.63 ± 0.009 mg/mL). The antioxidant potential of these plant extracts were also determined by using DPPH (2,2-diphenyl-1-picrylhydrazyl), iron chelation, and superoxide anion radical scavenging assays. Among five plants, Sida cordifolia exhibited a potent anti-oxidant activity in both DPPH and superoxide anion radical scavenging assays (IC50 = 0.005 ± 0.0004, and 0.078 ± 0.002 mg/mL, respectively), followed by Rosa indica (IC50 = 0.023 ± 0.0005 and 0.141 ± 0.003 mg/mL, respectively). CONCLUSIONS: Protein glycation in hyperglycemic conditions involve oxidative changes. Therefore dual inhibition of protein glycation and oxidation are desirable properties in any test substance investigated for therapeutic purposes.

Dihydropyrano [2,3-c] pyrazole: Novel in vitro inhibitors of yeast α-glucosidase.

Inhibition of α-glucosidase enzyme activity is a reliable approach towards controlling post-prandial hyperglycemia associated risk factors. During the current study, a series of dihydropyrano[2,3-c] pyrazoles (1-35) were synthesized and evaluated for their α-glucosidase inhibitory activity. Compounds 1, 4, 22, 30, and 33 were found to be the potent inhibitors of the yeast α-glucosidase enzyme. Mechanistic studies on most potent compounds reveled that 1, 4, and 30 were non-competitive inhibitors (Ki=9.75±0.07, 46±0.0001, and 69.16±0.01µM, respectively), compound 22 is a competitive inhibitor (Ki=190±0.016µM), while 33 was an uncompetitive inhibitor (Ki=45±0.0014µM) of the enzyme. Finally, the cytotoxicity of potent compounds (i.e. compounds 1, 4, 22, 30, and 33) was also evaluated against mouse fibroblast 3T3 cell line assay, and no toxicity was observed. This study identifies non-cytotoxic novel inhibitors of α-glucosidase enzyme for further investigation as anti-diabetic agents.

2-Arylquinazolin-4(3H)-ones: A new class of α-glucosidase inhibitors.

Twenty-five derivatives of 2-arylquinazolin-4(3H)-ones (1-25) were evaluated for their yeast (Saccharomyces cerevisiae) α-glucosidase inhibitory activities. All synthetic compounds, except 1 and 6, were found to be several hundred fold more active (IC50 values in the range of 0.3±0.01-117.9±1.76µM), than the standard drug, acarbose (IC50=840±1.73µM). The enzyme kinetic studies on the most active compounds 12, 4, 19, and 13 were performed for the determination of their modes of inhibition and dissociation constants Ki. Study of the modes of inhibition of compounds 12, and 4 were also performed using molecular modeling techniques. In brief, current study identifies a novel class of α-glucosidase inhibitors which can be further studied for the treatment of hyperglycemia and obesity.

Novel VPS13B Mutations in Three Large Pakistani Cohen Syndrome Families Suggests a Baloch Variant with Autistic-Like Features.

BACKGROUND: Cohen Syndrome (COH1) is a rare autosomal recessive disorder, principally identified by ocular, neural and muscular deficits. We identified three large consanguineous Pakistani families with intellectual disability and in some cases with autistic traits. METHODS: Clinical assessments were performed in order to allow comparison of clinical features with other VPS13B mutations. Homozygosity mapping followed by whole exome sequencing and Sanger sequencing strategies were used to identify disease-related mutations. RESULTS: We identified two novel homozygous deletion mutations in VPS13B, firstly a 1 bp deletion, NM_017890.4:c.6879delT; p.Phe2293Leufs*24, and secondly a deletion of exons 37-40, which co-segregate with affected status. In addition to COH1-related traits, autistic features were reported in a number of family members, contrasting with the "friendly" demeanour often associated with COH1. The c.6879delT mutation is present in two families from different regions of the country, but both from the Baloch sub-ethnic group, and with a shared haplotype, indicating a founder effect among the Baloch population. CONCLUSION: We suspect that the c.6879delT mutation may be a common cause of COH1 and similar phenotypes among the Baloch population. Additionally, most of the individuals with the c.6879delT mutation in these two families also present with autistic like traits, and suggests that this variant may lead to a distinct autistic-like COH1 subgroup.

Comparative anti-glycation and α-glucosidase inhibition studies of microbial transformed compounds of dydrogesterone.

Anti-glycation and α-glucosidase inhibition activities of microbial transformed compounds of dydrogesterone (1); 20R-hydroxy-9ß,10αa-pregna-4,6-diene-3-one (2), 17ß-hydroxy-9ß,10α-androsta-4,6-diene-3-one (3) and 9ß,10α-androsta-4,6-diene-3,17-dione (4) were evaluated. Compounds 1 and 4 showed potent α-glucosidase inhibitory activities, while 2 and 3 were found to be weak inhibitors, whereas anti-glycation activities of 1-4 were not observed.

CC2D1A regulates human intellectual and social function as well as NF-κB signaling homeostasis.

Autism spectrum disorder (ASD) and intellectual disability (ID) are often comorbid, but the extent to which they share common genetic causes remains controversial. Here, we present two autosomal-recessive "founder" mutations in the CC2D1A gene causing fully penetrant cognitive phenotypes, including mild-to-severe ID, ASD, as well as seizures, suggesting shared developmental mechanisms. CC2D1A regulates multiple intracellular signaling pathways, and we found its strongest effect to be on the transcription factor nuclear factor κB (NF-κB). Cc2d1a gain and loss of function both increase activation of NF-κB, revealing a critical role of Cc2d1a in homeostatic control of intracellular signaling. Cc2d1a knockdown in neurons reduces dendritic complexity and increases NF-κB activity, and the effects of Cc2d1a depletion can be rescued by inhibiting NF-κB activity. Homeostatic regulation of neuronal signaling pathways provides a mechanism whereby common founder mutations could manifest diverse symptoms in different patients.

Antiglycation activity of quinoline derivatives- a new therapeutic class for the management of type 2 diabetes complications.

We report here a new class of compounds, quinoline derivatives, as potential inhibitors of in vitro bovine serum albumin-methylglyoxal glycation. Among compounds 1-19, compound 14 was found to be the most active analog with IC50 of 282.98 ± 8.4 µM. Compounds 12 (IC50 = 661.78 ± 8.7 µM) and 15 (IC50 = 629.43 ± 7.85 7 µM) were also identified as modest inhibitors, in comparison to the standard inhibitor, rutin (IC50 = 294.50 ± 1.5 µM). When evaluated for antioxidant activity through in vitro DPPH radical scavenging assay, compounds 3 (IC50 = 2.19 ± 0.27 µM), 6 (IC50 = 7.35 ± 2.27 µM), 11 (IC50 = 8.96 ± 0.56 µM), and 12 (IC50 = 10.11 ± 2.03 µM), and 15 (IC50 = 7.01 ± 3.87 µM) were found to be more active than the standard i.e. gallic acid (IC50 = 23.34 ± 0.43 µM). These compounds were also evaluated for cytotoxicity against rat fibroblast cell line (3T3 cell line). All compounds were found to be non-toxic in cellular model. This study identifies quinoline derivatives as a new class of inhibitors of protein glycation in vitro, along with antioxidant and non-toxic nature. These properties make them interesting leads for further studies as potential anti-diabetic agents.

Structure-based design, synthesis and biological evaluation of ß-glucuronidase inhibitors.

Using structure-based virtual screening approach, a coumarin derivative (1) was identified as ß-glucuronidase inhibitor. A focused library of coumarin derivatives was synthesized by eco-benign version of chemical reaction, and all synthetic compounds were characterized by using spectroscopy. These compounds were found to be inhibitor of ß-glucuronidase with IC50 values in a micromolar range. All synthetic compounds exhibited interesting inhibitory activity against ß-glucuronidase, however, their potency varied substantially from IC50 = 9.9-352.6 µM. Of twenty-one compounds, four exhibited a better inhibitory profile than the initial hit 1. Interestingly, compounds 1e, 1k, 1n and 1p exhibited more potency than the standard inhibitor with IC50 values 34.2, 21.4, 11.7, and 9.9 µM, respectively. We further studied their dose responses and also checked our results by using detergent Triton ×-100. We found that our results are true and not affected by detergent.

Benzothiazole derivatives: novel inhibitors of methylglyoxal mediated glycation of proteins in vitro.

This manuscript describes the protein anti-glycation activity of thirty-three (33) benzothiazoles, out of which twenty-seven were the newly synthesized benzothiazoles. Compound 1 (IC50= 187 ± 2.6 µM) was found to be the most active, while compounds 2 (IC50= 219 ± 3.6 µM), 3 (IC50= 224 ± 1.9 µM), 4 (IC50= 223 ± 3.3 µM), 5 (IC50= 238 ± 2.2 µM), 7 (IC50= 266 ± 5.4 µM), 17 (IC50= 226 ± 1.6 µM) and 18 (IC50= 274 ± 2.4 µM) were significantly active, when compared with the standard rutin (IC50= 294 ± 1.5 µM). This study identified potential inhibitors of methylglyoxal mediated glycation of proteins, which is the pathophysiology of late diabetic complications.