Design, synthesis, evaluation and molecular modelling studies of some novel 5,6-diphenyl-1,2,4-triazin-3(2H)-ones bearing five-member heterocyclic moieties as potential COX-2 inhibitors: A hybrid pharmacophore approach.

A series of novel hybrids comprising of 1,3,4-oxadiazole/thiadiazole and 1,2,4-triazole tethered to 5,6-diphenyl-1,2,4-triazin-3(2H)-one were designed, synthesised and evaluated as COX-2 inhibitors for the treatment of inflammation. The synthesised hybrids were characterised using FT-IR, 1H NMR, 13C NMR, elemental (C,H,N) analyses and assessed for their anti-inflammatory potential by in vitro albumin denaturation assay. Compounds exhibiting activity comparable to indomethacin and celecoxib were further evaluated for in vivo anti-inflammatory activity. Oral administration of promising compounds 3c-3e and 4c-4e did not evoke significant gastric, hepatic and renal toxicity in rats. These potential compounds exhibited reduced malondialdehyde (MDA) content on the gastric mucosa suggesting their protective effects by inhibition of lipid peroxidation. Based on the outcome of in vitro COX assay, compounds 3c-3e and 4c-4e (IC50 0.60-1.11µM) elicited an interesting profile as competitive selective COX-2 inhibitors. Further, selected compounds 3e and 4c were found devoid of cardiotoxicity post evaluation on myocardial infarcted rats. The in silico binding mode of the potential compounds into the COX-2 active site through docking and molecular dynamics exemplified their consensual interaction and subsequent COX-2 inhibition with significant implications for structure-based drug design.

Synthesis, characterization, evaluation and molecular dynamics studies of 5, 6-diphenyl-1,2,4-triazin-3(2H)-one derivatives bearing 5-substituted 1,3,4-oxadiazole as potential anti-inflammatory and analgesic agents.

A series of triazin-3(2H)-one derivatives bearing 1,3,4-oxadiazole (4a-4o) were synthesized, characterized and evaluated for anti-inflammatory and analgesic activities. Preliminary in vitro anti-inflammatory activity was assessed using an albumin denaturation assay. The promising compounds were further evaluated in acute, sub-chronic and chronic animal models of inflammation. Derivatives 4d, 4e, 4g, 4j and 4l exhibited significant anti-inflammatory activity with reduced ulcerogenic, hepatotoxic and renotoxic liabilities compared to standard indomethacin. These potential derivatives were also evaluated for in vivo analgesic activity using a writhing model and the formalin-induced paw licking response in mice. Compounds 4d, 4e and 4g exhibited comparable analgesic activity, whereas 4j and 4l yielded moderate effects. The specificity of compounds 4d, 4e, 4g, 4j, and 4l to inhibit (cyclooxygenase-1) COX-1 and (cyclooxygenase-2) COX-2 isozymes and their kinetics were also determined via an in vitro COX inhibition assay. In silico docking studies were performed using a molecular dynamics simulation of the most active compound 4d (COX-2 IC50: 3.07 µM) at the COX-2 active site. The outcome of this exercise helped to verify the consensual interaction of these compounds with the enzyme.

Synthesis, cytotoxic evaluation, docking and in silico pharmacokinetic prediction of 4-arylideneamino/cycloalkylidineamino 1, 2-naphthoquinone thiosemicarbazones.

In an attempt to develop potent anticancer agents, a series of 4-arylideneamino/cycloalkylidineamino-1, 2-naphthoquinone thiosemicarbazones were synthesized and characterized using FT-IR, (1)H NMR, (13)C NMR spectroscopy and elemental analysis. The compounds were screened for antiproliferative activity against three human cancer cell lines (Hep-G2, MG-63 and MCF-7) using the MTT assay. Significant anticancer activity was observed for several members of the series. The compounds 4-(3, 4, 5-trimethoxybenzylidene amino) 1, 2-naphthoquinone-2-thiosemicarbazone (TS10) and 4-(4-hydroxy-3-methoxy benzylideneamino) 1, 2-naphthoquinone-2-thiosemicarbazone (TS13) were active cytotoxic agents in all three cancer cell lines, with IC50 values in the range of 3.5-6.4 µM. Further evaluation of some of these potent cytotoxic compounds demonstrated their good safety profile in a normal cell line (MCF-12A). Docking experiments showed a good correlation between the predicted glide scores and the IC50 values of these compounds. In silico ADME studies revealed that these compounds can be used for second generation development.

Synthesis, characterization, biological evaluation and docking of coumarin coupled thiazolidinedione derivatives and its bioisosteres as PPARγ agonists.

Thiazolidinedione (TZD) derivatives are the novel class of oral antidiabetic drugs which are selective agonist for the nuclear PPAR γ that enhances the transcription of several insulin responsive genes but TZDs are known to cause weight gain, hepatotoxicity and fluid retention. So a new series of coumarin coupled thiazolidinedione derivatives and its bioisosters (oxazolidinedione and imidazolidinedione) were synthesized by Knoevenagel condensation of 4-((7-hydroxy-2-oxo-2H-chromen-4-yl) methoxy) benzaldehyde with 2,4 thiazolidinedione and its bioisosteres. The structures of these compounds were established by means of FT IR, 1H-NMR, elemental analysis and mass spectroscopy. All the compounds were screened for antidiabetic activity in streptozotocin induced diabetic wistar male rats. Most of the compounds revealed significant antidiabetic activity when compared with the standard drug rosiglitazone. Compounds 5 & 6 containing oxazolidinedione ring system were found to be more active than compounds having thiazolidinedione and imidazolidinedione nucleus. Molecular docking was performed on 2 PRG protein by using the software Glide (Schrödinger, LLC, USA). The QikProp program was used to obtain the pharmacokinetic properties of analogues.

Antidiabetic and antioxidant effect of various fractions of Phyllanthus simplex in alloxan diabetic rats.

AIM OF THE STUDY: To evaluate the antidiabetic and antioxidant effects of various fractions of Phyllanthus simplex on alloxan induced diabetes in rats. MATERIALS AND METHODS: Hypoglycemic effect of Phyllanthus simplex fractions was evaluated in normal and diabetic rats. Diabetes was induced by intraperitoneal injection of alloxan monohydrate (120 mg/kg). Normal and diabetic rats were divided into different groups (six rats each group) and orally administered with petroleum ether (P.E.) (200 and 400 mg/kg), ethyl acetate (EtOAc) (100 and 200 mg/kg), methanol (125 and 250 mg/kg), water fraction (150 and 300 mg/kg) and glibenclamide (10 mg/kg) for 21 days. Blood samples were collected from overnight fasted normal rats on day 21, from overnight fasted diabetic rats at 7, 14 and 21 days of treatment and analyzed for blood glucose level. On day 22 blood samples were collected from diabetic rats to estimate biochemical parameters, rats were sacrificed by single stunning and tissues were excised to measure their antioxidant and glycogen status. RESULTS: In the normoglycemic rats, MeOH (125 and 250 mg/kg) and aqueous fractions (150 and 300 mg/kg) showed a significant (P<0.05) hypoglycemic effect on day 21. In diabetic control rats, MeOH (125 and 250 mg/kg) and aqueous fractions (150 and 300 mg/kg) showed significant antihyperglycemic effect (P<0.001). The active fractions (MeOH and aqueous) of Phyllanthus simplex also increased the body weight of diabetic rats significantly compared to the control group. The active fractions were able to normalize the marked alterations in antioxidant enzymes and antioxidant parameters levels in liver and kidney. Treatment with the active fractions also normalized the diabetic induced hyperlipidemia and liver glycogen. CONCLUSIONS: These results demonstrate the antidiabetic and antioxidant potential of fractions of Phyllanthus simplex and suggests that the plant may have therapeutic value in diabetes and related complications.