Arvind K. Srivastava

Pyranocoumarins: A new class of anti-hyperglycemic and anti-dyslipidemic agents

A series of pyranocoumarin derivatives were synthesized and evaluated in vivo for their anti-hyperglycemic as well as anti-dyslipidemic activities. Compounds 7a, 7c, 8a, 8b, 8c, 8e and 8f have shown promising anti-hyperglycemic activities in sucrose loaded model (SLM) as well as sucrose challenged streptozotocin induced diabetic rat model (STZ). Compounds 8a and 8b were showing 38.0% and 42.0% blood glucose lowering activity in db/db mice model. In vitro anti-hyperglycemic activity evaluation exhibited that compounds 8a (IC(50)=24.5 microM) and 8b (IC(50)=36.2 microM) are potential PTP-1B inhibitors thereby revealing their possible mechanism of anti-diabetic action. Compounds 7a, 7b, 8a, 8b, 8d, 8e and 8f have shown significant anti-dyslipidemic activity in triton induced dyslipidemia in rats.

Synthesis and bioevaluation of glycosyl ureas as α-glucosidase inhibitors and their effect on mycobacterium

Glycosyl amino esters (2-13) on reaction with different isocyanates resulted in quantitative conversion to glycosyl ureas (14--32). Few of the selected ureas (15-20, 22-28, 30 and 32) on cyclative amidation with DBU/TBAB/4 A MS gave respective dihydropyrimidinones in fair to good yields (33-47). The compounds were screened for alpha-glucosidase inhibitory activity and two (19 and 23) of them showed strong inhibition against rat intestinal alpha-glucosidase. The compounds were also screened against Mycobacterium aurum, however, only one (19) of them exhibited marginal antitubercular activity.

Synthesis and antihyperglycemic activity of suitably functionalized 3H-quinazolin-4-ones

A series of 2-sec-amino-3H-quinazolin-4-ones (4a-p) and 4-sec-amino-2-chloroquinazolines (5a-b) have been synthesized by nucleophilic substitution reaction of 2-chloro-4(3H)-quinazolones (3) and 2,4-dichloroquinazolines (2) with amines, respectively. Most of the synthesized compounds were evaluated for antihyperglycemic activity but only 4a,b,d,j,o displayed significant reduction in blood glucose level in streptozotocin and sucrose loaded rat models.

Synthesis of glycosylated β-amino acids as new class of antitubercular agents

Abstract A series of glycosylated β-amino acids was prepared and evaluated against Mycobacterium tuberculosis, M. avium, M. fortuitum and M. smegmatis. The compounds were designed to mimic the enzyme d -alanine racemase and glycosyl transferase involved in the biosynthesis of essential cell wall peptidoglycan and arabinogalactan. Though most of the compounds exhibited little activity, however, one showed significant activity against all the strains in cell culture and activity was confirmed by B actec method.

Coagulanolide, a withanolide from Withania coagulans fruits and antihyperglycemic activity☆

One new withanolide, (17S,20S,22R)-14alpha,15alpha,17beta,20beta-tetrahydroxy-1-oxowitha-2,5,24-trienolide) named coagulanolide (4) along with four known withanolides 1-3 and 5 have been isolated from Withania coagulans fruits and their structures were elucidated by spectroscopic techniques. The compounds 1-5 showed significant inhibition on postprandial rise in hyperglycemia post-sucrose load in normoglycemic rats as well as streptozotocin-induced diabetic rats. The compound 5 also showed significant fall on fasting blood glucose profile and improved the glucose tolerance of db/db mice. Further compound 5 showed antidyslipidemic activity in db/db mice. The median effective dose of the compound 5 was determined to be around 25 mg/kg in streptozotocin-induced diabetic rats, which is comparable to the standard antidiabetic drug metformin. Our results provide further support to explain the traditional use of W. coagulans as antihyperglycemic cum antidyslipidemic agent by the traditional medical practitioners.

Design and synthesis of 2,4-disubstituted polyhydroquinolines as prospective antihyperglycemic and lipid modulating agents.

A series of 2,4-disubstituted polyhydroquinoline were synthesized and evaluated for their in vivo antihyperglycemic as well as antidyslipidemic activities. Several synthesized compounds have exhibited promising in vivo antihyperglycemic in SLM, STZ-S, and db/db mice model along with significant lipid and TG modulating activity. All these compounds were evaluated in various in vitro models of diabetes to know the possible mechanism of their antihyperglycemic action. Interestingly, compounds 3a-r (diaryl substitution) have exhibited promising protein-tyrosine phosphatase 1B (PTP1B) inhibitory activity whereas, compounds 5a-d (acid substituted) have shown significant glycogen phosphorylase activity.

Hepatoprotective potential of Fumaria indica Pugsley whole plant extracts, fractions and an isolated alkaloid protopine

The present investigation demonstrates the hepatoprotective potential of 50% ethanolic water extract of whole plant of Fumaria indica and its three fractions viz., hexane, chloroform and butanol against d-galactosamine induced hepatotoxicity in rats. The hepatoprotection was assessed in terms reduction in histological damage, changes in serum enzymes (SGOT, SGPT, ALP) and metabolites bilirubin, reduced glutathione (GSH) and lipid peroxidation (MDA content). Among fractions more than 90% protection was found with butanol fraction in which alkaloid protopine was quantified as highest i.e. about 0.2mg/g by HPTLC. The isolated protopine in doses of 10-20mg p.o. also proved equally effective hepatoprotectants as standard drug silymarine (single dose 25mg p.o.). In general all treatments excluding hexane fraction proved hepatoprotective at par with silymarine (p<or=0.01).

Synthesis of novel triterpenoid (lupeol) derivatives and their in vivo antihyperglycemic and antidyslipidemic activity.

The triterpenoid, lupeol (1) has been isolated from the leaves extract of Aegle marmelos. Few novel derivatives (2-13) were synthesized from the naturally occurring lupeol (1) and screened for their antihyperglycemic activity (2-11) and antidyslipidemic activity (2-4 and 12-13). The derivative 4 lowered the blood glucose levels by 18.2% and 25.0% at 5h and 24h, respectively, in sucrose challenged streptozotocin induced diabetic rats (STZ-S) model at the dose of 100mg/kg body weight. The compound 4 also significantly lowered 40% (P <0.001) in triglycerides, 30% (P <0.05) in glycerol, 24% (P <0.05) in cholesterol quantity and also improved the HDL-cholesterol by 5% in dyslipidemic hamster model at the dose of 50mg/kg b.wt.

Identification of pongamol and karanjin as lead compounds with antihyperglycemic activity from Pongamia pinnata fruits

AIM OF THE STUDY To identify pongamol and karanjin as lead compounds with antihyperglycemic activity from Pongamia pinnata fruits. MATERIAL AND METHODS Streptozotocin-induced diabetic rats and hyperglycemic, hyperlipidemic and hyperinsulinemic db/db mice were used to investigate the antihyperglycemic activity of pongamol and karangin isolated from the fruits of Pongamia pinnata. RESULTS In streptozotocin-induced diabetic rats, single dose treatment of pongamol and karanjin lowered the blood glucose level by 12.8% (p<0.05) and 11.7% (p<0.05) at 50mg /kg dose and 22.0% (p<0.01) and 20.7% (p<0.01) at 100mg/kg dose, respectively after 6h post-oral administration. The compounds also significantly lowered blood glucose level in db/db mice with percent activity of 35.7 (p<0.01) and 30.6 (p<0.01), respectively at 100mg/kg dose after consecutive treatment for 10 days. The compounds were observed to exert a significant inhibitory effect on enzyme protein tyrosine phosphatase-1B (EC 3.1.3.48). CONCLUSION The results showed that pongamol and karangin isolated from the fruits of Pongamia pinnata possesses significant antihyperglycemic activity in Streptozotocin-induced diabetic rats and type 2 diabetic db/db mice and protein tyrosine phosphatase-1B may be the possible target for their activity.

Application of click chemistry towards an efficient synthesis of 1,2,3-1H-triazolyl glycohybrids as enzyme inhibitors

An efficient synthesis of novel 1,2,3-1H-triazolyl glycohybrids with two or more than two sugar units or a chromenone moiety via copper-catalysed azide-alkyne cycloaddition (CuAAC), a 1,3-dipolar cycloaddition of glycosyl azides to 2,3-unsaturated alkynyl glycosides or propargyloxy coumarins is described. The synthesised glycohybrids were screened for their α-glucosidase, glycogen phosphorylase and glucose-6-phosphatase inhibitory activities. A few of the glycohybrids showed promising inhibitory activities against these enzymes.