Saima Rasheed

Synthesis of bis-Schiff bases of isatins and their antiglycation activity

Bis-Schiff bases 1-27 have been synthesized and their in vitro antiglycation potential has been evaluated. Compounds 21 (IC(50)=243.95+/-4.59microM), 20 (IC(50)=257.61+/-5.63microM), and 7 (IC(50)=291.14+/-2.53microM) showed an excellent antiglycation activity better than the standard (rutin, IC(50)=294.46+/-1.50microM). This study has identified a series of potential molecules as antiglycation agents. A structure-activity relationship has been studied, and all the compounds were characterized by spectroscopic techniques.

Oxindole Derivatives: Synthesis and Antiglycation Activity

Oxindole derivatives 3-25 have been synthesized from commercially available oxindole by refluxing with different aromatic aldehydes in good yields. Their in vitro antiglycation potential has been evaluated. They showed a varying degree of antiglycation activity with IC50 values ranging between 150.4 - 856.7 µM. 3-[(3-Chlorophenyl)methylidene]- 1,3-dihydro-2H-indol-2-one (IC50 = 150.4 ± 2.5 µM) is the most active compound among the series, better than the standard rutin with an IC50 value 294.5 ± 1.50 µM. The structures of the compounds were elucidated by 1H-NMR and mass spectroscopy and elemental analysis. A limited structure-activity relationship has been developed.

Synthesis of 4-Methoxybenzoylhydrazones and Evaluation of Their Antiglycation Activity

A series of 4-methoxybenzoylhydrazones 1–30 was synthesized and the structures of the synthetic derivatives elucidated by spectroscopic methods. The compounds showed a varying degree of antiglycation activity, with IC50 values ranging between 216.52 and 748.71 µM, when compared to a rutin standard (IC50 = 294.46 ± 1.50 µM). Compounds 1 (IC50 = 216.52 ± 4.2 µM), 3 (IC50 = 289.58 ± 2.64 µM), 6 (IC50 = 227.75 ± 0.53 µM), 7 (IC50 = 242.53 ± 6.1) and 11 (IC50 = 287.79 ± 1.59) all showed more activity that the standard, and these compounds have the potential to serve as possible leads for drugs to inhibit protein glycation in diabetic patients. A preliminary SAR study was performed.

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.

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.

Metronidazole Esters: A New Class of Antiglycation Agents

A series of metronidazole ester derivatives 1-34 has been synthesized with the aim of developing new leads with antiglycation activity. The in vitro evaluation of antiglycation potential of 1-34 showed that the ester derivatives 28, 16, and 3 have IC(50) values 218.97 ± 2.5, 245.3 ± 5.1, and 278.6 ± 0.8 µM, respectively, comparable to the standard agent, rutin (IC(50) = 294.5 ± 1.50 µM). The study identifies a new class of potent antiglycation agents. A structure-activity relationship has also been evaluated. All the compounds were characterized by using spectroscopic techniques, including (1)H NMR, IR, and EI-MS.

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.

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.

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 11β, 12β-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 11β,12β-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.