Design, synthesis, in vitro antiproliferative evaluation and GSK-3ß kinase inhibition of a new series of pyrimidin-4-one based amide conjugates.

A new series of novel amide conjugates of pyrimidin-4-one and aromatic/heteroaromatic /secondary cyclic amines has been synthesized and their in vitro antiproliferative activities against a panel of 60 human cancer cell lines of nine different cancer types were tested at NCI. Among the synthesized compounds, compound (4i) showed significant anti-proliferative activity. Compound (4i) displayed most potent activity against the breast tumor cell line T-47D and CNS tumor cell line SNB-75 exhibiting a growth of 1.93 % and 14.63 %, respectively. ADMET studies of the synthesized compounds were also performed and they were found to exhibit good drug like properties. Compound (4i) was found to exhibit potential inhibitory effect over GSK-3ß with IC50 value of 71 nM. The molecular docking studies revealed that (4i) showed good binding affinity to GSK-3ß and revealed multiple H-bonding and p-cation interactions with important amino acid residues on the receptor site. Compound (4i) may thus serve as a potential candidate for further development of novel anticancer therapeutics.

In silico designing, in vitro and in vivo evaluation of potential PPAR-γ agonists derived from aryl propionic acid scaffold.

Attributed to several side effects, especially on hepatic tissues and body weight, there is always an urge of innovation and upgrading in already existing medication being used in maintaining diabetic condition. Therefore, in the present work, forty-eight molecules derived from arylpropionic acid scaffold were synthesized and their evaluation against diabetes was carried out. The synthesis of these molecules attributed to excellent dock score displayed by all the structures performed against PPAR-γ receptor site. Subsequently, all the derivatives were primarily deduced for their antidiabetic potential by OGTT. The compounds that showed significant antidiabetic activity in OGT Test and also exhibited high dock scores were assessed further by in vitro PPAR transactivation assay to assure analogy between in vivo and in vitro studies. The antidiabetic activity of these active compounds was then evaluated on STZ induced diabetic model in vivo. The most active compounds were scrutinized for its effect on PPAR-γ gene expression and hepatotoxic effect. Finally, it was recapitulated that these derivatives can provide a new prospect towards the development of antidiabetic agents with fewer side effects.

Synthesis of benzimidazole-linked-1,3,4-oxadiazole carboxamides as GSK-3ß inhibitors with in vivo antidepressant activity.

Recent findings of potential implications of glycogen synthase kinase-3ß (GSK-3ß) dysfunction in psychiatric disorders like depression, have increased focus for development of GSK-3ß inhibitors with possible anti-depressant activity. Keeping this in view, we synthesized a series of benzimidazole-linked-1,3,4-oxadiazole carboxamides and evaluated them for in vitro GSK-3ß inhibition. Active compounds were investigated for in vivo antidepressant activity in Wistar rats. Docking studies of active compounds have also been performed. Among nineteen compounds synthesized, compounds 7a, 7r, 7j, and 7d exhibited significant potency against GSK-3ß in sub-micromolar range with IC50 values of 0.13 µM, 0.14 µM, 0.20 µM, 0.22 µM respectively and significantly reduced immobility time (antidepressant-like activity) in rats compared to control group. Docking study showed key interactions of these compounds with GSK-3ß. These compounds may thus serve as valuable candidates for subsequent development of effective drugs against depression and related disorders.

Novel 2,4-dichlorophenoxy acetic acid substituted thiazolidin-4-ones as anti-inflammatory agents: Design, synthesis and biological screening.

A library of fourteen 2-imino-4-thiazolidinone derivatives (1a-1n) has been synthesized and evaluated for in vivo anti-inflammatory activity and effect on ex-vivo COX-2 and TNF-α expression. Compounds 1k (5-(2,4-dichloro-phenooxy)-acetic acid (3-benzyl-4-oxo-thiazolidin-2-ylidene)-hydrazide) and 1m (5-(2,4-dichloro-phenooxy)-acetic acid (3-cyclohexyl-4-oxo-thiazolidin-2-ylidene)-hydrazide) exhibited in vivo inhibition of 81.14% and 78.80% respectively after 5h in comparison to indomethacin which showed 76.36% inhibition of inflammation without causing any damage to the stomach. Compound 1k showed a reduction of 68.32% in the level of COX-2 as compared to the indomethacin which exhibited 66.23% inhibition of COX-2. The selectivity index of compound 1k was found to be 29.00 in comparison to indomethacin showing selectivity index of 0.476. Compounds 1k and 1m were also found to significantly suppress TNF-α concentration to 70.10% and 68.43% in comparison to indomethacin which exhibited 66.45% suppression.

Oxazolo[4,5-b]pyridine-Based Piperazinamides as GSK-3ß Inhibitors with Potential for Attenuating Inflammation and Suppression of Pro-Inflammatory Mediators.

Recent studies reveal that glycogen synthase kinase-3ß (GSK-3ß) acts as a pro-inflammatory enzyme, and by inhibiting this kinase, inflammation can be controlled. In this regard, a series of 17 piperazine-linked oxazolo[4,5-b]pyridine-based derivatives was synthesized and evaluated for in vitro GSK-3ß inhibitory and in vivo anti-inflammatory activity. The compounds 7d, 7e, 7g, and 7c displayed the best GSK-3ß inhibitory activity among all the synthesized compounds, with corresponding IC50 values of 0.34, 0.39, 0.47, and 0.53 µM. Among the compounds 7d, 7e, 7g, and 7c examined for in vivo anti-inflammatory activity in the rat paw edema model, compound 7d exhibited maximum inhibition, reducing the paw volume by 62.79 and 65.91% at 3 and 5 h post-carrageenan administration, respectively, in comparison to indomethacin (76.74% at 3 h and 79.54% at 5 h after carrageenan administration). Furthermore, these compounds (7d, 7e, 7g, and 7c) were also found to substantially inhibit pro-inflammatory mediators, i.e., TNF-α, IL-1ß, and IL-6, ex vivo in comparison to indomethacin and did not pose any gastric ulceration risk, indicating the potential of this oxazolopyridine scaffold for the development of GSK-3ß inhibitors and their application as anti-inflammatory agents.

Synthesis of benzimidazole based thiadiazole and carbohydrazide conjugates as glycogen synthase kinase-3ß inhibitors with anti-depressant activity.

A series of benzimidazole based thiadiazole and carbohydrazide conjugates have been synthesized and evaluated for inhibition of glycogen synthase kinase-3ß and anti-depressant effect. Compounds 4f, 4j, 5b, 5g and 5i were found to be the most potent inhibitors of GSK-3ß in vitro amongst the twenty-five benzimidazole based thiadiazole and carbohydrazide conjugates synthesized. Compound 5i was also found to exhibit significant antidepressant activity in vivo at 50mg/kg, when compared to fluoxetine, a known antidepressant drug. The molecular docking studies revealed multiple hydrogen bond interactions by the synthesized compounds with various amino acid residues, viz, ASP-133, LYS-183, PRO-136, VAL-135, TYR-134, or LYS-60 at the GSK-3ß receptor site.

Synthesis of pyrimidin-4-one-1,2,3-triazole conjugates as glycogen synthase kinase-3ß inhibitors with anti-depressant activity.

GSK-3 specific inhibitors are promising candidates for the treatment of devastating pathologies such as diabetes, neurodegenerative diseases and cancers. We have synthesized a library of pyrimidin-4-one-1,2,3-triazole conjugates using click-chemistry approach and evaluated them as glycogen synthase kinase-3ß inhibitors. Compounds 3g, 3j, 3n and 3r were found to be most potent among the eighteen pyrimidin-4-one-1,2,3-triazole conjugates synthesized and they were further evaluated for their in vivo anti-depressant activity. Compound 3n (2-((1-(3,4-dimethylphenyl)-1H-1,2,3-triazol-4-yl)methylthio)-3-methyl-6-phenylpyrimidin-4(3H)-one) exhibited the most potent inhibitory activity against GSK-3ß with IC50 value of 82nM and was also found to exhibit significant antidepressant activity at 50mg/kg, when compared with fluoxetine, a known antidepressant drug. The molecular docking studies were performed to elucidate the binding modes of the compounds with the GSK-3ß target and two crucial interactions namely, hydrogen bond formation with Val 135 and Lys 183 residues in the active site of GSK-3ß were observed.

Antidiabetic effect of novel benzenesulfonylureas as PPAR-γ agonists and their anticancer effect.

Twenty one pyrazoline containing benzenesulfonylureas were synthesized and docked against PPAR-γ target. All the compounds were first screened for their antidiabetic potential by oral glucose tolerance test and then six active compounds were assessed on STZ diabetic model. It was found that five compounds showed significantly high antidiabetic activity in comparison to glibenclamide as well as rosiglitazone (standard drugs). The active compounds were evaluated for their effect on body weight since weight management is one of the main concerns associated with sulfonylureas. Finally, the most active compound 6f was shown to elevate PPAR-γ gene expression. The synthesized compounds were also screened for anticancer activity by National Cancer Institute. Five compounds (5i, 6e, 6g, 6i and 6j) were selected at one dose level and showed potency against cancers.

Ameliorative effects of Trichosanthes dioica Extract in suppressing inflammatory mediators and attenuating oxidative stress.

The present study aimed to investigate the anti-inflammatory activity of the ethanolic extract of the aerial parts of Trichosanthes dioica and its successive fractions. The effect on oxidative stress involved in the pathogenesis of inflammation was evaluated. The ethanolic extract and its successive fractions were administered at a dose of 150 and 300 mg/kg b. w. for testing their anti-inflammatory activity by a carrageenan-induced edema model. The results showed that the ethyl acetate fraction exhibited significant potency against inflammation. Pertaining to mechanistic insight, the anti-inflammatory effect might be attributed to the attenuation in tumor necrosis factor-α level (ELISA assay) and reduced expression of cyclooxygenase-2 and nuclear transcription factor-κB (immunohistochemistry). The alleviation in oxidative stress has been pertinent to the elevation in the activities of antioxidant enzymes (superoxide dismutase, catalase, and glutathione) by active fractions. Furthermore, the ulcerogenic effect was insignificant even at a three times higher dose. Finally, it was concluded that the ethyl acetate fraction which showed significant biological potential against inflammation and oxidative stress could be viewed as a source of effective treatment.

Design, Synthesis, and Biological Evaluation of Thiazolidine-2,4-dione Conjugates as PPAR-γ Agonists.

A library of synthesized conjugates of phenoxy acetic acid and thiazolidinedione 5a-m showed potent peroxisome proliferator activated receptor-γ (PPAR-γ) transactivation as well as significant blood glucose lowering effect comparable to the standard drugs pioglitazone and rosiglitazone. Most of the compounds showed higher docking scores than the standard drug rosiglitazone in the molecular docking study. Compounds 5l and 5m exhibited PPAR-γ transactivation of 54.21 and 55.41%, respectively, in comparison to the standard drugs pioglitazone and rosiglitazone, which showed 65.94 and 82.21% activation, respectively. Compounds 5l and 5m significantly lowered the blood glucose level of STZ-induced diabetic rats. Compounds 5l and 5m lowered the AST, ALT, and ALP levels more than the standard drug pioglitazone. PPAR-γ gene expression was significantly increased by compound 5m (2.00-fold) in comparison to the standard drugs pioglitazone (1.5-fold) and rosiglitazone (1.0-fold). Compounds 5l and 5m did not cause any damage to the liver and could be considered as promising candidates for the development of new antidiabetic agents.

Novel benzenesulfonylureas containing thiophenylpyrazoline moiety as potential antidiabetic and anticancer agents.

In the present study a library of twenty six benzenesulfonylureas containing thiophenylpyrazoline moiety has been synthesized. All the compounds were docked against PPAR-γ target. Most of the compounds displayed higher dock score than standard drugs, glibenclamide and rosiglitazone. All the synthesized compounds were primarily evaluated for their antidiabetic effect by oral glucose tolerance test. Further assessment of antidiabetic potential of sixteen active compounds was then done on STZ induced diabetic model. The results of in vivo activity by both the methods were found to be consistent with each other as well as with docking studies. Change in body weight of STZ induced animals post treatment was also assessed at the end of study. In vitro PPAR-γ transactivation assay was performed on active compounds in order to validate docking results and the most active compound 3 k was also shown to elevate gene expression of PPAR-γ. Furthermore, the compounds were screened by National Cancer Institute, Bethesda for anticancer effect and two compounds 3h and 3 i were selected at one dose level since they exhibited sensitivity towards tumor cell lines (mainly melanoma).

Thiazolidine-2,4-diones derivatives as PPAR-γ agonists: synthesis, molecular docking, in vitro and in vivo antidiabetic activity with hepatotoxicity risk evaluation and effect on PPAR-γ gene expression.

A library of conjugates of chromones and 2,4-thiazolidinedione has been synthesized by Knoevenagel condensation followed by reduction using hydrogen gas and Pd/C as a catalyst. Compounds 5c and 5e were most effective in lowering the blood glucose level comparable to standard drug pioglitazone. Compound 5e exhibited potent PPAR-γ transactivation of 48.72% in comparison to pioglitazone (62.48%). All the molecules showed good glide score against the PPAR-γ target in molecular docking study. PPAR-γ gene expression was significantly increased by compound 5e (2.56-fold) in comparison to standard drug pioglitazone. Compounds 5e and 5c did not cause any damage to the liver and may be considered as promising candidates for the development of new antidiabetic agents.

Synthesis and evaluation of pyrazolines bearing benzothiazole as anti-inflammatory agents.

The present study aims at the synthesis of pyrazolines bearing benzothiazole and their evaluation as anti-inflammatory agents. The synthesized compounds were evaluated for their anti-inflammatory potential using carrageenan induced paw edema model. Two compounds 5a and 5d alleviated inflammation more than the standard drug celecoxib. Eight compounds 5 b, 5 c, 5 e, 5 g, 5 h, 6 b, 6 e and 6 f showed anti-inflammatory activity comparable to celecoxib. To understand the mode of action, COX-2 enzyme assay and TNF-α assay were carried out. All the active compounds were assessed for their cytotoxicity. The ulcerogenic risk evaluation was performed on the active compounds that were not found to be cytotoxic. Out of ten active compounds, two compounds (5 d and 6 f) were finally found to be the most potent anti-inflammatory agents attributing to the suppression of the COX-2 enzyme activity and TNF-α production without being either cytotoxic or ulcerogenic.

Design and Synthesis of Benzimidazole Carboxamide Cysteine Protease Inhibitors as Promising Anti-leishmanial Agents.

INTRODUCTION: More than 20 protozoan species of Leishmania are responsible for causing Leishmaniasis, an infection spread by blood-feeding phlebotomine sandflies. A narrow pool of drugs is currently available rendering the current drug stratagem to treat this infection . Development of novel, less toxic, and more effective regimens is thus a need of the hour. Design and synthesis of benzo[d]imidazole carboxamides as agents to combat Leishmaniasis are also required. METHODS: 14 benzo[d]imidazole carboxamides were synthesized and gauged against L. donovani promastigotes and intramacrophage amastigote forms. All of the tested compounds exhibited significant anti-promastigote properties with IC50 well below 10 uM. Compounds 4a, 4b, and 4d, showing the highest anti-parasitic activity against promastigote forms (IC50 0.91- 1.33 µM), were also found to be associated with better anti-leishmanial potential (IC50 0.78- 1.67 µM) against the intramacrophage amastigotes comparable to Amphotericin-B (0.13 µM), a drug used for Leishmaniasis. Compound (4a), namely N-(2-(trifluoromethyl)-1Hbenzo[ d]imidazol-5-yl)benzo[d][1,3]-5-carboxamide-dioxole, was found to be most potent against L. donovani amastigotes among all the tested compounds, and demonstrated better antileishmanial properties (IC50 0.78 µM) when compared to the standard. Compound 4a was also assessed for its toxicity profile against THP-1 human monocytic cells. To establish the molecular target(s) in silico, molecular docking studies were performed against cysteine protease, a putative virulence factor of Leishmania parasites, and nucleoside diphosphate kinase, an enzyme with a critical role in nucleotide recycling, also associated with resistance in Leishmania strains. Compound 4a showed better binding affinity than the standard to these targets; furthermore, the molecular dynamic simulation studies further affirmed the stability of compound 4a, within the active site of the targets. In vitro, cysteine protease inhibitory activity (IC50 8.53 µM) using Bz-Arg-AMC hydrochloride fluorogenic peptide substrate established the promising potential of 4a as a cysteine protease inhibitor. RESULT: Computational ADMET analysis indicated appropriate pharmacokinetic profile and physicochemical characteristics for all members of the synthesized library. CONCLUSION: Both in vitro and in silico studies indicate that the synthesized imidazole carboxamides can act as potent hits and that N-(2-(trifluoromethyl)-1H-benzo[d]imidazol-5- yl)benzo[d][1,3]-5-carboxamide-dioxole 4a can be an effective hit molecule which can be further developed into potent lead molecule (s) to fight Leishmania donovani.

Synthesis and biological evaluation of some novel sulfamoylphenyl-pyridazinone as anti-inflammatory agents (Part-II * ).

Seven novel 6-aryl-2-(p-sulfamoylphenyl)-4,5-dihydropyridazin-3(2H)-ones (2a-g) were synthesized by the condensation of appropriate aroylpropionic acid and 4-hydrazinobenzenesulfonamide hydrochloride in ethanol. Structure of all compounds have been elucidated by elemental analysis, IR, (1)H NMR, (13)C NMR, DEPT and MS spectrscopy. These compounds were tested for their anti-inflammatory activity in carrageenan-induced rat paw edema model. Compound 2b exhibited anti-inflammatory activity comparable to that of celecoxib (at 5 h). Two other compounds 2d and 2g showed promising anti-inflammatory activity (edema reduction more than 80% at 5 h). These compounds (2b, 2d and 2g) did not produce any ulceration in gastric region.

Synthesis of some new s-alkylated 1,2,4-triazoles, their mannich bases and their biological activities.

A series of 1-(4-methoxyphenyl)-2-[5-{(biphenyl-4-yloxy)methyl}4-(substituted phenyl)-3-mercapto-(4H)-1,2,4-triazol-3-ylthio)] ethanones (6a-6s) and 4-(substituted phenyl)-3-(morpholin/pyrrolidin-4-ylmethylthio)-5-(4-phenylphenoxymethyl)-4H-1,2,4-triazoles (7a-7e) were synthesized in order to obtain new compounds with potent anti-inflammatory and analgesic activity with insignificant ulceration. Among the synthesized compounds, (6c), (6e), (6g) and (6l) from triazole series and (7b) and (7e) from Mannich base series were found to exhibit significant anti-inflammatory activity with 59.69, 59.69, 64.69, 79.84, 54.54, 79.69% and 52.55, 57.50, 72.52, 83.03, 60.06, 84.08% inhibition of paw edema at 3 h and 5 h respectively, in comparison to the standard drug ibuprofen (78.93 and 82.58% at 3 h and 5 h). The active compounds were further tested for their analgesic activity and gastric ulceration study. Compounds 6g, 7b and 7e exhibited significant analgesic activity with reaction time (3.60, 3.22, 3.88 s) respectively at 60 min. without causing any gastric irritation. These compounds were also screened for their in vitro antimicrobial activity, Compounds 6f, 6g, 6h, 6l, 6o, 6p, 7a, 7b and 7c showed significant zone of inhibition against various antimicrobial stains. It is concluded that the compounds 6g, 7b and 7e possess a good spectrum of activities. Compound 7e may be considered potent for development of better anti-inflammatory agent. The antimicrobial activity revealed that most of the compounds showed moderate to significant activity. Compounds containing nitro, chloro, bromo and fluoro group showing better activity. All the compounds from 7a, 7b and 7e were active against gram positive bacteria (S. aureus).

Nanotechnology-based approaches applied to nutraceuticals.

Nutraceuticals and food industries are opening to a tremendously upcoming technology in the field of "Nano science". A new prospect has been defined by nanotechnology by conferring modified properties of nanomaterials and its application in the development of nanoformulations, nutritional supplements and food industry. Nanomaterials reveal exclusive properties because of their small size and high surface/volume ratio; thus, they have a complete application in nutraceuticals and food sector. In the existent review article, we obligate to present a comprehensive outline of the application of nanomaterials in development of advanced nano-based nutraceuticals with enhanced bioavailability, solubility, improved encapsulation efficiency, increased stability, sustained and targeted drug delivery, protection against degradation and microbial contamination and with improved pharmacological activity. It also highlights the importance of nanomaterials as nanosensors/nano-bio sensors for encapsulating peptides, antibodies, enzymes, etc. and in the food packaging industry and its future application. Thus, the review aims to focus on the benefits and new dimensions provided by nanomaterials and nanotechnology in health sectors by improving treatment strategies and quality of life.

Synthesis of some new 1,3,5-trisubstituted pyrazolines bearing benzene sulfonamide as anticancer and anti-inflammatory agents.

Thirteen new 2-pyrazoline derivatives bearing benzenesulfonamide moiety (2a-m) were synthesized by condensing appropriate chalcones with 4-hydrazinonbenzenesulfonamide hydrochloride and tested for anticancer and anti-inflammatory actions. According to the protocol of the National Cancer Institute (NCI) in vitro disease-oriented human cells screening panel assay compounds 2b, 2c, 2e, 2f and 2g exhibited considerable antitumor activities against the entire tested tumor cell lines and showed effective growth inhibition GI(50) (MG-MID) values of 2.63, 2.57, 6.61, 3.31 and 2.57µM, respectively, beside a cyclostatic activity TGI (MG-MID) 9.54, 8.51, 24.0, 19.9 and 8.71µM, respectively. Two compounds 2g and 2k showed more potent anti-inflammatory activity than celecoxib at 5h in carrageenan-induced rat paw edema bioassay. These compounds (2g and 2k) proved to have superior gastrointestinal safety profiles as compared to celecoxib, when tested for their ulcerogenic effects. Compounds 2g and 2k showed no inhibition against the enzymatic activity of bovine COX-2 (in vitro).

Chemical constituents with antimicrobial and antioxidant activity from the aerial parts of Callistemon lanceolatus (Sm.) Sweet.

Callistemon lanceolatus (Sm.) Sweet grows all over the world and used to treat cough and bronchitis. The air-dried powder of the aerial parts was exhaustively extracted with methanol and the concentrated extract was adsorbed on silica gel for preparation of slurry. It was dried and subjected to silica gel column packed in petroleum ether. The column was eluted with organic solvents in order of increasing polarity to isolate 1-triacosanol (1), n-eicosanyl palmitate (2), n-heptadecanyl arachidate (3), n-tricosanyl palmitate, (4), 4-hydroxyphenethyl carbocerate (5), 4-hydroxyphenethyl gheddate (6), urs-12-en-3α-acetoxy-18ß-H-28-oic acid (7) and stigmast-5-en-3ß-ol-3ß-D-glucuronopyranoside (8). Among them, compound 5 and 6 were new fatty acid ester isolated from this plant. Compound 7 showed MIC 32 µg/mL against E. coli which was comparable to amoxicillin having same MIC 32 µg/mL. Compound 5 and 6 showed significant antioxidant activity by inhibiting DPPH due to the presence of phenolic groups.

Design, synthesis and biological evaluation of benzoxazolinone-containing 1,3,4-thiadiazoles as TNF-α inhibitors.

A library of nineteen benzoxazolinone-based 1,3,4-thiadiazoles has been synthesized and screened for their anti-inflammatory activity. The compound 1f exhibited a potent anti-inflammatory activity with an inhibition of 65.83% and 32.50% after 3 h and 5 h respectively. It also exhibited a significant in vitro (p < 0.01), TNF- α inhibitory activity with 51.44 % inhibition. The compound 1f showed hydrogen bonding with GLN 61 and interactions with TYR 119, TYR 151 and GLY 121. The histopathology report showed that none of the compounds caused gastric ulceration. The results from the in vivo & in vitro antiinflammatory activity along with In Silico studies exhibit that benzoxazolinone-based 1,3,4-thiadiazoles may be used in the future development of anti-inflammatory drugs.