Investigations on substituted (2-aminothiazol-5-yl)(imidazo[1,2-a]pyridin-3-yl)methanones for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease majorly affecting old age populations. Various factors that affect the progression of the disease include, amyloid plaque formation, neurofibrillary tangles, inflammation, oxidative stress, etc. Herein we report of a new series of substituted (2-aminothiazol-5-yl)(imidazo[1,2-a]pyridin-3-yl)methanones. The designed compounds were synthesized and characterized by spectral data. In vivo anti-inflammatory activity was carried out for screening of anti-inflammatory potential of synthesized compounds. All the compounds were tested for acute inflammatory activity by using carrageenan induced acute inflammation model. Compounds 10b, 10c, and 10o had shown promising acute anti-inflammatory activity and they were further tested for formalin induced chronic inflammation model. Compound 10c showed both acute and chronic anti-inflammatory activity. Compound 10c also showed promising results in AlCl3 induced AD model. Studies on various behavioral parameters suggested improved amnesic performance of compound 10c treated rats. Compound 10c treated rats also exhibited excellent antioxidant and neuroprotective effect with inherent gastrointestinal safety.

Pharmacological investigation of quinoxaline-bisthiazoles as multitarget-directed ligands for the treatment of Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent disease of old age leading to dementia. Complex AD pathogenesis involves multiple factors viz. amyloid plaque formation, neurofibrillary tangles and inflammation. Herein we report of a new series of quinoxaline-bisthiazoles as multitarget-directed ligands (MTDLs) targeting BACE-1 and inflammation concurrently. Virtual screening of a library of novel quinoxaline-bisthiazoles was performed by docking studies. The most active molecules from the docking library were taken up for synthesis and characterized by spectral data. Compounds 8a-8n showed BACE-1 inhibition in micro molar range. One of the compounds, 8n showed BACE-1 inhibition at IC50 of 3 ±â€¯0.07 µM. Rat paw edema inhibition in acute and chronic models of inflammation were obtained at 69 ±â€¯0.45% and 55 ±â€¯0.7%, respectively. Compound 8n also showed noteworthy results in AlCl3 induced AD model. The treated rats exhibited excellent antiamnesic, antiamyloid, antioxidant, and neuroprotective properties. Behavioural parameters suggested improved cognitive functions which further validates the testimony of present study. Moreover, compound 8n was found to have inherent gastrointestinal safety. This new string of quinoxaline-bisthiazoles were identified as effective lead for the generation of potent MTDLs and compound 8n was found to showcase qualities to tackle AD pathogenesis.

Thiazolyl-thiadiazines as Beta Site Amyloid Precursor Protein Cleaving Enzyme-1 (BACE-1) Inhibitors and Anti-inflammatory Agents: Multitarget-Directed Ligands for the Efficient Management of Alzheimer's Disease.

Alzheimer's disease (AD) is associated with multiple neuropathological events including ß-site amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibition and neuronal inflammation, ensuing degeneracy, and death to neuronal cells. Targeting such a complex disease via a single target directed treatment was found to be inefficacious. Hence, with an intention to incorporate multiple therapeutic effects within a single molecule, multitarget-directed ligands (MTDLs) have been evolved. Herein, for the first time, we report the discovery of novel thiazolyl-thiadiazines that can serve as MTDLs as evident from the in vitro and in vivo studies. These MTDLs exhibited BACE-1 inhibition down to micromolar range, and results from the in vivo studies demonstrated efficient anti-inflammatory activity with inherent gastrointestinal safety. Moreover, compound 6d unveiled noteworthy antioxidant, antiamyloid, neuroprotective, and antiamnesic properties. Overall, results of the present study manifest the potential outcome of thiazolyl-thiadiazines for AD treatment.

Stability-indicating assay method for determination of actarit, its process related impurities and degradation products: Insight into stability profile and degradation pathways☆.

The stability of the drug actarit was studied under different stress conditions like hydrolysis (acid, alkaline and neutral), oxidation, photolysis and thermal degradation as recommended by International Conference on Harmonization (ICH) guidelines. Drug was found to be unstable in acidic, basic and photolytic conditions and produced a common degradation product while oxidative stress condition produced three additional degradation products. Drug was impassive to neutral hydrolysis, dry thermal and accelerated stability conditions. Degradation products were identified, isolated and characterized by different spectroscopic analyses. Drug and the degradation products were synthesized by a new route using green chemistry. The chromatographic separation of the drug and its impurities was achieved in a phenomenex luna C18 column employing a step gradient elution by high performance liquid chromatography coupled to photodiode array and mass spectrometry detectors (HPLC-PDA-MS). A specific and sensitive stability-indicating assay method for the simultaneous determination of the drug actarit, its process related impurities and degradation products was developed and validated.

New insight into adenosine receptors selectivity derived from a novel series of [5-substituted-4-phenyl-1,3-thiazol-2-yl] benzamides and furamides.

A series of [5-substituted-4-phenyl-1,3-thiazol-2-yl] benzamide and furamide analogues were investigated in radioligand binding studies at adenosine receptor subtypes with an aim to obtain potent and selective adenosine receptor ligands. Benzamide and furamide linked to thiazole was found to be crucial for high adenosine receptor affinity. The most potent compound indentified in this study was 5d with low nanomolar affinity for all four adenosine receptor subtypes. Compounds 5a and 5g showed moderate selectivity for A2A adenosine receptors. Molecular docking versus all four human adenosine receptors combined with membrane molecular dynamics studies were performed to rationalise the peculiar selectivity profile of 5d antagonist.

Beneficial effects of swertiamarin on dyslipidaemia in streptozotocin-induced type 2 diabetic rats.

Dyslipidaemia is one of the major risk factors for cardiovascular disease in diabetes mellitus. Lipid changes associated with diabetes mellitus are attributed to increases in free fatty acid flux, secondary to insulin resistance. In the present study, we have investigated the beneficial effects of swertiamarin on dyslipidaemic conditions associated with type 2 diabetes in streptozotocin-induced type 2 diabetic rats. Swertiamarin (50 mg/kg, i.p.) administered once a day for 6 weeks resulted in significant (p < 0.001) reductions in serum triglycerides, cholesterol and low-density lipoprotein levels in diabetic animals as compared with diabetic control animals. Serum fasting glucose was significantly (p < 0.05) decreased, moreover, the insulin sensitivity index was significantly (p < 0.05) increased in swertiamarin treated animals. Overall the data suggest that swertiamarin has beneficial effects on diabetic associated complications such as dyslipidaemia.

Synthesis and evaluation of quinazolinone derivatives as inhibitors of NF-kappaB, AP-1 mediated transcription and eIF-4E mediated translational activation: inhibitors of multi-pathways involve in cancer.

In our effort to discover and develop small molecule multi-pathway inhibitors which may be useful as tools for treating cancerous conditions, we have synthesized a small library of 2-thiazole-5-yl-3H-quinazolin-4-one derivatives. Synthesized compounds were evaluated as inhibitors of NF-kappaB and AP-1 mediated transcriptional and eIF-4E mediated translational activation as these transcription and translation factors are known to play a pivotal role in initiation and progression of cancer. The results from the study suggest the utility of the 2-thiazole-5-yl-3H-quinazolin-4-one scaffold as a promising scaffold for the design of novel multi-pathway inhibitors, which can be explored as anti-cancer agents.

2-Amino-5-benzoyl-4-phenylthiazoles: Development of potent and selective adenosine A1 receptor antagonists.

A series of 2-amino-5-benzoyl-4-phenylthiazole derivatives was investigated in radioligand binding studies at adenosine receptor (AdoR) subtypes with the goal to obtain potent and A(1)-selective antagonists. Acylation of the 2-amino group was found to be crucial for high A(1) affinity. The best compound of the present series was 2-benzoylamino-5-p-methylbenzoyl-4-phenylthiazole (16 m) showing a K(i) value of 4.83 nM at rat and 57.4 nM at human A(1) receptors combined with high selectivity versus the other AdoR subtypes. The compound behaved as an antagonist in GTP shift assays at A(1) receptors. Compound 16 m may serve as a new lead structure for the development of second-generation non-xanthine-derived A(1) antagonists which have potential as novel drugs.

Design, synthesis and evaluation of novel 2-thiophen-5-yl-3H-quinazolin-4-one analogues as inhibitors of transcription factors NF-kappaB and AP-1 mediated transcriptional activation: Their possible utilization as anti-inflammatory and anti-cancer agents.

In an attempt to discover novel inhibitors of NF-kappaB and AP-1 mediated transcriptional activation utilizing the concept of chemical lead based medicinal chemistry and bioisosterism a series of 2-(2,3-disubstituted-thiophen-5-yl)-3H-quinazolin-4-one analogs was designed. A facile and simple route for the synthesis of the designed molecules was developed. Synthesized molecules were evaluated for their activity as inhibitors towards NF-kappaB and AP-1 mediated transcriptional activation in a cell line report-based assay. This series provides us with a substantial number of compounds inhibiting the activity of NF-kappaB and/or AP-1 mediated transcriptional activation. These compounds also exhibit anti-inflammatory and anti-cancer activity in in vivo models of inflammation and cancer. The 4-pyridyl group is found to be the most important pharmacophore on the third position of thiophene ring for inhibiting NF-kappaB and AP-1 mediated transcriptional activation. The relationships between the activities shown by these compounds in the in vivo and in vitro models have been established by using FVB transgenic mice model. These results suggest the suitability of the designed molecular framework as a potential scaffold for the design of molecules with inhibitory activity towards NF-kappaB and AP-1 mediated transcriptional activation, which may also exhibit anti-inflammatory and anti-cancer activity. This series of molecules warrants further study to explore their potential as therapies for use in chronic inflammatory conditions and cancer. Development of the synthetic protocol for the synthesis of this series of molecules, biological activities and a structure-activity relationship (SAR) have been discussed herein.

Antihyperlipidaemic activity of swertiamarin, a secoiridoid glycoside in poloxamer-407-induced hyperlipidaemic rats.

We have investigated antihyperlipidaemic effect of swertiamarin (50 mg/kg, oral once) isolated from the perennial herb Enicostemma littorale Blume in poloxamer 407 (P-407)-induced hyperlipidaemic rats. Rats were made hyperlipidaemic by intraperitoneal administration of P-407 (400 mg/kg). Serum lipid levels such as total cholesterol, triglycerides and low-density lipoprotein cholesterol increased significantly (P < 0.001) compared with normal control rats. All these changes were significantly prevented in the rats treated with swertiamarin. Serum high-density lipoprotein (HDL) cholesterol was found to be reduced in the P-407 control rats. However, administration of swertiamarin significantly (P < 0.01) increased HDL levels and it showed a significant lipid-lowering effect, as well as a high antiatherogenic potential. Overall swertiamarin is an effective lipid-lowering lead compound and can be useful for preventing atherosclerosis.

Swertiamarin: a lead from Enicostemma littorale Blume. for anti-hyperlipidaemic effect.

We have investigated the hypolipidemic effects of swertiamarin an active lead isolated from a perennial herb Enicostemma littorale Blume. in high cholesterol fed rats. Swertiamarin (50 and 75 mg/kg) and atorvastatin (50 mg/kg) was given orally daily for seven consecutive day to the high cholesterol feed rats. Serum total cholesterol, triglycerides, low density lipoprotein and very low density lipoprotein were found to be markedly elevated in the high cholesterol fed control rats and these changes were significantly prevented in swertiamarin treated animals. However, there was no significant effect on serum high density lipoprotein level. The 3-hydroxy 3-methyl glutaryl Co A (HMG-Co A) reductase activity was significantly inhibited in swertiamarin and atorvastatin treated groups compared to high cholesterol fed control group. Swertiamarin was also found to increased excretion of fecal bile acid and total sterols compared to control animals. In conclusion our data suggest that swertiamarin possess high antiatherogenic potential and an effective cholesterol lowering agent and inhibition of HMG-Co A reductase may be one of the main mechanisms of hypolipidemic effect of swertiamarin.

Synthesis, anti-inflammatory, analgesic and antioxidant activities of some tetrasubstituted thiophenes.

Sets of tetrasubstituted thiophene esters 4a-4g, 5a-5f and 6a-6e were synthesized by reaction of 1-(alpha-Carbomethoxy-beta-aminothiocrotonoyl)-aryl/aroyl amines (3) with 3-(bromoacetyl)coumarin, 1,4-dibromodiacetyl and chloroacetone respectively. The compound 3 were synthesized by nucleophilic addition of aryl/aroylisothiocyanate and enamine (2). The synthesized targeted compounds (4a-4g, 5a-5f and 6a-6e) were evaluated for their in vivo anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at three graded doses employed at 10, 20 and 40 mg/kg body weight using mefanamic acid, ibuprofen and in vivo analgesic activity in acetic acid induced writhing response model at 10 mg/kg dose using ibuprofen as standard drug. The compounds 4a-4f, 5c, 5f, 6c and 6e were evaluated for their in vitro antioxidant nitric oxide radical scavenging assay at the concentrations of 5, 10, 15, 20, 25, 30 and 35 microg/mL using ascorbic acid as standard drug. Among all the targeted compounds 4c showed maximum anti-inflammatory activity of 71% protection at 10 mg/kg and 77% protection at 20 mg/kg to inflamed paw and analgesic activity of 56% inhibition and also maximum in vitro nitric oxide radical scavenging activity having IC(50) value 31.59 microg/mL.

Design, synthesis and pharmacological evaluation of novel tetrasubstituted thiophene analogues as anti-inflammatory agents.

A new series of tetrasubstituted thiophene analogues (4a-4f, 5a-5f and 8a-8i) were designed incorporating the pharmacophoric features of COX-1 (as in fenamates), 5-LOX and the p38 MAP kinase inhibitors. The designed series was synthesized by nucleophilic addition of aryl/aroylisothiocyanate and enamine (2) yielding the addition product l-(alpha-Carbomethoxy-beta-aminothiocrotonoyl)-aryl/aroyl amines (3/7); which on reaction with substituted phenacyl bromides gave the targeted tetrasubstituted thiophene esters (4a-4f / 8a-8i). The tetrasubstituted thiophenes esters (4a-4f ) on hydrolysis with one equivalent of potassium hydroxide solution in methanol at room temperature gave corresponding acids (5a-5f ). All the targeted compounds were evaluated for their anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at the doses of 10, 20 and 40 mg/kg body weight using standard drugs mefanamic acid and ibuprofen. The compounds (4c, 4e, 4f, 5f, 8a- 8i) which gave reasonable protection to the inflamed paw, eliciting good or moderate comparable anti-inflammatory activity were selected for investigating their analgesic activity using acetic acid induced writhing response test in albino mice at 10 mg/kg dose using standard drug ibuprofen and in order to arrive at possible mechanism of their anti-inflammatory activity, in vitro antioxidant nitric oxide radical scavenging assay at the concentrations of 5, 10, 15, 20, 25, 30 and 35 microg/mL were performed using standard drug ascorbic acid.

Syntheses of new tetrasubstituted thiophenes as novel anti-inflammatory agents.

A series of new tetrasubstituted thiophenes (4a-4i, 5a-5i and 6a-6f) have been synthesized as novel anti-inflammatory agents and were evaluated for their anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at the doses of 10, 20 and 40mg/kg body weight. Among ester series, the best compound 4c showed 71% protection at 10mg/kg, 72% at 20mg/kg, and 76% at 40mg/kg to inflamed paw; while in acid series 5a showed 79% protection at 10mg/kg, 80% at 20mg/kg, and 70% at 40mg/kg, and 5c showed 72% protection at 10mg/kg, 75% at 20mg/kg, and 69% at 40mg/kg, to inflamed paw. In case of oxime series 6a-6f, the anti-inflammatory activities of the candidates were found to be poor as compared to acid and ester series. It was found on the basis of SAR studies of target compounds, that the presence of OCH(3) at R(2) position and H, OCH(3) at R(1) are one of the requirements for eliciting comparable anti-inflammatory activity in both tetrasubstituted thiophenes' ester and acid series. Compounds 4a-4i, 5a-5i were investigated for their analgesic activity in acetic acid induced writhing response model at 10mg/kg dose. Among the ester series compound 4e showed maximum protection of 60%, while 4a, 4b, and 4i exhibited 55%, 45%, and 43% protection, respectively. The result showed that presence of H, Cl at R(1) and OCH(3), CH(3) at R(2) in tetrasubstituted thiophene ester series enhances their analgesic activity. The candidates of acid series 5a-5i showed poor analgesic activity as compared to the standard drug ibuprofen. Compounds 4a-4i, 5a-5i were evaluated for their in vitro antioxidant nitric oxide radical scavenging assay. Among the ester series 4a showed maximum in vitro nitric oxide radical scavenging activity having IC(50) value 30.08microg/ml while in acid series 5a has IC(50) value 25.20microg/ml. The results showed that the presence of R(1)=H, R(2)=OCH(3) and R(1)=R(2)=OCH(3) enhances nitric oxide radical scavenging property in tetrasubstituted thiophenes' acid series.

Tetra substituted thiophenes as anti-inflammatory agents: exploitation of analogue-based drug design.

A series of 17 novel tetra substituted thiophenes was designed, synthesized, and screened for anti-inflammatory activity in carrageenin induced rat paw edema model, an acute in vivo model. The lead molecule selected was Tenidap, a dual COX/LOX inhibitor. Compounds I (43%), III (60%), IV (60%), and VIII (64%) showed moderate to good anti-inflammatory activity. The best candidate among the whole series was VIII, which gave 64% protection to the inflamed paw. The side chain of candidate VIII had resemblance to that of Romazarit, a DMARD, which was withdrawn due to its toxicity profile. A probable reason for the metabolic stability of the proposed side chain not having the possibility of generating peroxy type radicals or acrylic acid moieties, unlike Romazarit, is discussed. The biological activity exhibited by the three designed series was in the order of methyl amino series > ethyl amino series > carbethoxy amino series. The -(C=O)-CH2-COOR side chain at the fifth position as in candidate VIII, the methyl amino group at the second position, and the ester at the third position of the thiophene can be considered as a three-point pharmacophore for designing better anti-inflammatory agents. The present study is a classical example of the exploitation of an analogue based drug design, which culminated in the development of good anti-inflammatory agents that have the potential of becoming dual inhibitors.

QSAR studies on some thiophene analogs as anti-inflammatory agents: enhancement of activity by electronic parameters and its utilization for chemical lead optimization.

Small molecule heterocycle is an integral part of new drug discovery in anti-inflammatory research. In our previous papers we reported the synthesis of thiophene analogs substituted at the fifth position with alpha-oximino propionic ester moiety and the fact that such new chemical entities exhibit anti-inflammatory activity in male/female Sprague-Dawley rats. In this paper we report the quantitative structure activity relationship (QSAR) studies of a series of 43 thiophene analogs. The analogs when subjected to cluster analysis technique led to the formation of four homogeneous groups. The cluster analysis technique grouped the 2-anilino-5-substituted-4-methyl-thiophene-3-carboxylic acid methyl esters as one homogeneous group. The clusters were individually taken up for a Hansch type of QSAR study with 10 molecular descriptors. The QSAR equations generated were cross validated by the leave out one method. The studies gave an insight into the dominant role played by electronic properties like energy of the lowest unoccupied molecular orbital (ELUMO) and dipole moment (dipole) in modulating the anti-inflammatory activity. From the QSAR studies a three point pharmacophore has been established for designing novel anti-inflammatory molecules.

Design, synthesis, and pharmacological evaluation of some 2-[4-morpholino]-3-aryl-5-substituted thiophenes as novel anti-inflammatory agents: generation of a novel anti-inflammatory pharmacophore.

Compounds incorporating a thiophene moiety, a pi excess five membered heterocycle, have attracted a great deal of research interest owing to the therapeutic utility of the template as useful drug molecular scaffolding. Recently we reported the anti-inflammatory activity profile exhibited by two thiophene analogs, AP84 and AP82 in acute and chronic models of inflammation. The good activity profile exhibited by AP84, a 3-(substituted aryl)-2-(4-morpholino)-5-heteroaryl substituted analog of thiophene, in the formalin induced rat paw edema chronic model as compared to a weak activity in acute carrageenin induced rat paw edema, and the slightly better protection exhibited in the acute model by AP82 (27%), the 5-aroyl analog provided an impetus for a proper exploration of their structural types. In this paper we report the synthesis and pharmacological evaluation of some novel, 2-(4-morpholino)-3-(substituted aryl)-5-substituted thiophenes, as possible anti-inflammatory leads. The 3-(4-chlorophenyl)-2-(4-morpholino) thiophene analogs AP49, AP158, and AP88 provided a protection of 20%, 23%, and 20%, respectively, when screened for anti-inflammatory activity in carrageenin induced rat paw edema, an acute in vivo model, comparable to that of AP82, at a dose level of 100mg/kg body weight p.o. compared to ibuprofen as standard. The replacement of the 3-(4-chlorophenyl) moiety with the 3-phenyl moiety gave rise to AP50 (30%), AP159 (38%), AP27 (0%), and AP92 (38%), with three analogs being more active in the acute model. Alteration of the group para to the phenyl ring at third position, from chloro, to methyl mercapto gave rise to the 3-(4-methylmercapto-phenyl) analogs AP54 (20%), AP160 (0%), and AP73 (52%), with only one analog appearing to be better than AP82. These results indicate that 4-methane sulfonyl aroyl group at 5-position and other substituents of different quadrants of Craig plot on the phenyl moiety at the third position could lead to more potent candidates. However, alteration of aroyl to substituted pyridyl at 5-position with a phenyl group at the third position as in AP26 gave rise to much better protection (66%) again reinforcing the importance of the heteroaryl ring at the fifth position and implying its utility in the composition of a novel pharmacophore for designing better trisubstituted thiophenes as anti-inflammatory agents.

Novel drug designing approach for dual inhibitors as anti-inflammatory agents: implication of pyridine template.

Compounds incorporating thiophene moiety, a pi excess five membered heterocycle, have attracted a great deal of research interest, owing to the therapeutic utility of the template as useful drug molecular scaffolding. We report the synthesis and pharmacological evaluation of thiophenes substituted with 4-methanesulfonyl benzoyl moiety at the fifth position of the ring, as possible anti-inflammatory lead candidates. The aryl sulfonyl methyl thiophene analogs AP29, AP82, and AP37, when screened for anti-inflammatory activity in carrageenin induced rat paw edema, an acute in vivo model, exhibited moderate to good activity at a dose level of 100 mg/kg body weight P.o compared to Ibuprofen. In a five day formalin induced rat paw edema, a chronic in vivo anti-inflammatory model, candidates AP29, AP82, and AP37 inhibited the disease progression by 53%, 34%, and 65%, respectively on the fifth day, at a dose level of 100 mg/kg body weight P.o compared to Rofecoxib, Ibuprofen, and Dexamethasone at therapeutic doses which gave a protection of 53.8%, 81.5%, and 81.5%, respectively. The replacement of the 4-methanesulfonyl benzoyl moiety in AP82 with the pyridine template, 3,5-dimethyl-4-methoxy-2-pyridyl function, gave rise to AP84, which was less active in the acute model, but gave 54% and 75% protection both during the first day and fifth day, respectively, in the chronic model. A dual mechanism of action is proposed for AP84, a non-steroidal drug which has exhibited remarkable activity when compared to the steroid dexamethasone. These results open up new avenues in designing novel anti-inflammatory drugs as dual inhibitors with the incorporation of a pyridine template as part of the pharmacophore.