3D-QSAR studija afiniteta vezanja na receptor za (R,S)-2-amino-3-(3-hidroksi-5-metilizoksazol-4-il)-propansku kiselinu

An approach for binding affinity evaluation is suggested and exemplified using a set of triazolo [1,5-a] quinoxaline for the (R,S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)-propionic acid (AMPA) receptor. Biological activity toward the AMPA receptor (expressed as -log IC5O) was taken as a dependent variable for building Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) models. The resulting models show the ways of increasing the binding affinity to the AMPA receptor as a potential target for epilepsy. The statistically significant results show that the cross-validated r2CV value (0.766) for the CoMFA model is greater than (0.758) for the CoMSIA model. The non-cross validated run giving the coefficient of determination r2 values of 0.944 and 0.919 for CoMFA and CoMSIA, respectively, provided good correlation between the observed and computed affinities of the training set compounds. The resulting CoMFA and CoMSIA models indicate that steric, electrostatic, hydrophobic (lipophilic), hydrogen bond donor and acceptor substituents play a significant role in increasing the binding affinity and selectivity of the compounds toward the AMPA receptor.U radu je vrednovan afinitet vezanja serije triazolo[1,5-a]kinoksalina na receptor za (R,S)-2-amino-3-(3-hidroksi-5-metilizoksazol-4-il)-propansku kiselinu (AMPA). Djelovanje na AMPA receptor (izraženo kao log IC5O) uzeta je kao zavisna varijabla u modelima usporedne analize molekulskih polja (Comparative Molecular Field Analysis, CoMFA) i usporedne analize molekulske sličnosti (Comparative Molecular Similarity Indices Analysis, CoMSIA). Ti modeli pokazuju kako povećati afinitet vezanja na AMPA receptor, što može biti korisno u terapiji epilepsije. Statistički značajni rezultati ukazuju da je križno validirana r2CV vrijednost za CoMFA model (0,766) veća nego za CoMSIA model (0,758). Koeficijenti r2 za CoMFA model (0,944) i CoMSIA (0,919) ukazuju na dobru korelaciju između izračunatih i eksperimentalno određanih afiniteta vezanja proučavane serije spojeva. Prema oba modela za povećanje afiniteta vezanja i selektivnost spojeva za AMPA receptor značajna su sterička, elektrostatska, hidrofobna (lipofilni) svojstva, te sposobnost stvaranja vodikovih veza

Design and synthesis of bioisosteric tetrasubstituted thiophenes as novel anti-inflammatory agents: Part-I

Fourteen novel tetrasubstituted thiophene esters (VIIIa-VIIIg) and the corresponding acid derivatives (IXa- IXg) were designed, synthesized, characterized and evaluated for their anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at doses of 10, 20 and 40 mg/kg body weight. The designed compounds have the pharmacophoric features of COX-1 (acid/ester, as in mefenamic acid), 5-LOX and the p38 MAP kinase inhibitors. In the present study we report the optimization of electron withdrawing groups in the bioisosteric tetrasubstituted thiophenes at the para position in anilino moiety (R3) and in benzoyl moiety (R2) falling in +σ , ±π quadrant of the Craig plot and the effect on their anti-inflammatory activity. The reaction was brought about by reacting equimolar amount of the enamine (II) with arylisothiocyanates to yield the addition products (III), which on reaction with substituted phenacyl bromides (V) gave tetrasubstituted thiophene esters (VIIIa-VIIIg). The corresponding acids (IXa-IXg) of the tetrasubstituted thiophene esters (VIIIa-VIIIg) were prepared by hydrolyzing the methyl ester in methanol with one equivalent of potassium hydroxide solution at room temperature. All the synthesized compounds were evaluated for their anti-inflammatory activity. Compounds VIIIe (30%), VIIIf (55%), VIIIg (54%), IXc (37%), IXf (70%) and IXg (46%) showed moderate to good activity at a dose of 20 mg/kg when compared with the activity of ibuprofen (33%). The most active compound among the whole series was IXf, a bioisosteric analogue of mefenamic acid which showed 63% protection at 10 mg/kg, 70% at 20 mg/kg, and 60% at 40 mg/kg to inflamed paw. These results indicate that the presence of 2,4-Cl2 substitution at R2 position in tetrasubstituted thiophenes is one of the requirements for eliciting comparable antiinflammatory activity in both the ester and acid series. VIIIf, VIIIg, IXf and IXg were also tested for their analgesic activity in acetic acid-induced writhing response in albino mice at a dose of 10 mg/kg and showed 15%, 35%, 10% and 32% inhibition, respectively. Keywords: tetrasubstituted thiophenes, COX- inhibitors, p38 MAP kinase inhibitors, anti-inflammatory activity, analgesic activityEthiopian Pharmaceutical Journal Vol. 24, 2006: 1-1

Synthesis, Antiinflammatory and HIV-1 Integrase Inhibitory Activities of 1,2-Bis[5-thiazolyl]ethane-1,2-dione Derivatives

Based on principles of pharmacophore delineation and drug designing, compounds containing diketofunctionallity namely 1,2-bis[5-thiazolyl]ethane-1,2-diones were designed and synthesized as antiinflammatory agents. The compounds were evaluated in carrageenan-induced rat-paw edema method. G-3, G-6, G-17, G-20, G-23, G-22, L-708 and 906 showed good antiinflammatory activity. In addition as diketo functionality containing compounds are reported to have HIV-1 integrase inhibitory property, and these compounds contains diketo functionality, so these compounds were screened in assay for HIV-1 integrase inhibition. Few compounds showed weak HIV-1 integrase Inhibitory activity

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

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 (HPLCâPDAâMS). 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. Keywords: Actarit, Forced degradation, Stability-indicating assay metho

Discovery of 2-aminoimidazole and 2-amino imidazolyl-thiazoles as non-xanthine human adenosine A 3 receptor antagonists: SAR and molecular modeling studies

A small-molecule combinatorial library of 24 compounds with 2-aminoimidazole and 2-aminoimidazolyl-thiazole derivatives was synthesized using a 2-chloro trityl resin. The generated compound library was tested against all the human adenosine receptors subtypes. The 2-aminoimidazole derivatives (6a-6l) showed weak to moderate affinity towards the human adenosine receptors. Further modification to 2-aminoimidazolyl-thiazole derivatives (12a-12l) resulted in an improvement of affinity at adenosine A 1 , A 2A and A 3 receptor subtypes. Compound 12b was the most potent and selective non-xanthine human adenosine A 3 receptor antagonist of this series. A receptor-based modeling study was performed to explore the possible binding mode of these novel 2-aminoimidazole and 2-aminoimidazolyl-thiazole derivatives into human adenosine A 1 , A 2A and A 3 receptor subtypes

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 β-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 <i>in vitro</i> and <i>in vivo</i> studies. These MTDLs exhibited BACE-1 inhibition down to micromolar range, and results from the <i>in vivo</i> studies demonstrated efficient anti-inflammatory activity with inherent gastrointestinal safety. Moreover, compound <b>6d</b> unveiled noteworthy antioxidant, antiamyloid, neuroprotective, and antiamnesic properties. Overall, results of the present study manifest the potential outcome of thiazolyl-thiadiazines for AD treatment