3D-QSAR CoMFA/CoMSIA studije derivata 5-aril-2,2-dialkil-4-fenil-3(2H)-furanona, kao selektivnih COX-2 inhi

Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were performed on a series of 5-aryl-2,2-dialkyl-4-phenyl-3(2H)-furanone derivatives, as selective cyclooxygenase-2 (COX-2) inhibitors. Ligand molecular superimposition on the template structure was performed by the atom/shape based root mean square fit and database alignment methods. Removal of three outliers from the initial training set of 49 molecules improved the predictivity of the model. The statistically significant model was established of 36 molecules, which were validated by a test set of ten compounds. The atom and shape based root mean square alignment (IV) yielded the best predictive CoMFA model R2cv = 0.664, R2 (non-cross-validated square of correlation coefficient) = 0.916, F value = 47.341, R2bs = 0.947 with six components, standard error of prediction36 = 0.360 and standard error of estimate36 = 0.180 while the CoMSIA model yielded R2cv = 0.777, R2 (non-cross-validated square of correlation coefficient) = 0.905, F value = 66.322, R2bs = 0.933 with four components, standard error of prediction36 = 0.282 and standard error of estimate36 = 0.185. The contour maps obtained from 3D-QSAR studies were appraised for activity trends for the molecules analyzed. Results indicate that steric, electrostatic, hydrophobic (lipophilic) and hydrogen bond donor substituents play a significant role in COX-2 inhibitory activity and selectivity of the compounds. The data generated from the present study will further help design novel, potent and selective COX-2 inhibitors.Komparativna molekularna analiza polja (CoMFA) i komparativna analiza sličnosti molekularnih indeksa (CoMSIA) provedena je na seriji derivata 5-aril-2,2-dialkil-4-fenil-3(2H)-furanona kao selektivnih inhibitora ciklooksigenaze-2 (COX-2). Superimpozicija molekularnih liganada na uzorak strukture provedena je prilagodbom korijena usrednjenih kvadratnih udaljenosti temeljenih na udaljenostima atoma i na obliku molecule i metodom poravnavanja unutar skupa podataka. Uklanjanjem tri spoja koji jako odstupaju iz početnog skupa od 49 molekula povećala se točnost predviđanja modela. Postavljen je statistički značajan model od 36 molekula, koji je provjeren na dodatnom skupu od deset spojeva. Prilagodba korijena usrednjenih kvadratnih udaljenosti temeljenih na udaljenostima atoma i na obliku molekule dala je najbolji CoMFA model sa 6 komponenata koji ima R2cv = 0,664 (križno provjereni kvadrat koeficijenata korelacije), R2 = 0,916, F vrijednost = 47, 341, kod kojega je standardna pogreška predviđanja 0,360 i standardna pogreška procjene 0,180. Za CoMSIA model sa 4 komponente dobiveni su parametri R2cv = 0,777, R2 = 0,905, F vrijednost 66,322, standardna pogreška predviđanja 0,282 i standardna pogreška procjene 0,185. Iz mapa obrisa dobivenih 3D-QSAR studijom procijenjeni su trendovi aktivnosti za analizirane molekule. Rezultati ukazuju da sterički, elektrostatski, hidrofobni (lipofilni) supstituenti i oni koji mogu tvoriti vodikovu vezu imaju značajnu ulogu u inhibitornom djelovanju na COX-2 i selektivnost spojeva. Podaci dobiveni ovom studijom pomoći će u dizajniranju novih, snažnih i selektivnih COX-2 inhibitora

Istraživanja 3,4-diaril-1,2,5-oksadiazola i njihovih N-oksida: Potraga za boljim COX-2 inhibitorima

A series of 3,4-diaryl-1,2,5-oxadiazoles and 3,4-diaryl-1,2,5-oxadiazole N-oxides were prepared and evaluated for COX-2 and COX-1 binding affinity in vitro and for anti-inflammatory activity by the rat paw edema method. p-Methoxy (p-OMe) substituted compounds 9, 21, 34, 41, 42 showed COX-2 enzyme inhibition higher than that showed by compounds with other substituents. 3,4-Di(4-methoxyphenyl)-1,2,5-oxadiazole N-oxide (42) showed COX-2 enzyme inhibition of 54% at 22 µmol L-1 and COX-1 enzyme inhibition of 44% at 88 µmol L-1 concentrations, but showed very low in vivo anti-inflammatory activity. Its deoxygenated derivative (21) showed lower COX-2 enzyme inhibition (26% at 22 µmol L-1) and higher COX-1 enzyme inhibition (53% at 88 µmol L-1) but marked in vivo anti-inflammatory activity (71% at 25 mg kg-1) vs. celecoxib (48% at 12.5 mg kg-1). Molecular modeling (docking) studies showed that the methoxy group is positioned in the vicinity of the COX-2 secondary pocket and it also participates in hydrogen bonding interactions in the COX-2 active site. These preliminary studies suggest that the p-methoxy (p-OMe) group in one of benzene rings may give potentially active leads in this series of oxadiazole/N-oxides.Sintetizirana je serija 3,4-diaril-1,2,5-oksadiazola i 3,4-diaril-1,2,5-oksadiazol N-oksida i ocijenjena njihova sposobnost vezivanja na COX-2 i COX-1 in vitro i protuupalno djelovanje na edem šape štakora. Spojevi sa p-metoksi (p-OMe) supstituentom 9, 21, 34, 41, 42 bolje su inhibirali COX-2 nego ostali spojevi. 3,4-Di(4-metoksifenil)-1,2,5-oksadiazol N-oksid (42) inhibirao je COX-2 za 54% u koncentraciji od 22 µmol L-1, a COX-1 za 44% u koncentraciji 88 µmol L-1, ali je in vivo slabo djelovao protuupalno. Njegov deoksigenirani derivat 21 pokazao je slabiju inhibiciju COX-2 enzima (26% u koncentraciji 22 µmol L-1) i jaču inhibiciju COX-1 (71% u koncentraciji 25 mg kg-1) što je bolje od standarda celekoksiba (48% u koncentraciji 12,5 mg kg-1). Molekularno je modeliranje pokazalo da je metoksi skupina smještena u blizini sekundarnog džepa na enzimu COX-2 i da utječe na vodikove veze interakcija na aktivnom mjestu COX-2. Ova preliminarna istraživanja sugeriraju da bi se u seriji oksadiazol/N-oksida mogao naći predvodni spoj s p-metoksi skupinom na benzenskom prstenu

Improved percutaneous delivery of some NSAIDs for the treatment of arthritis

Arthritis is a heterogeneous group of conditions that leads to joint symptoms and signs which are associated with defective integrity of articular cartilage. Major classes of drugs which are widely used for the treatment of arthritis are Non-Steroidal Anti-inflammatory Drugs (NSAIDs). Development of an efficient means of percutaneous delivery can increase drug concentration in local soft-tissues and joints while reducing the systemic distribution of a drug and its side effects. The present work is aimed at synthesisand evaluation of prodrugs of some NSAIDs for percutaneous drug delivery for the treatment of arthritis

New azasteroidal neuromuscular blocking agent possessing acetylcholine- like moiety in ring -A

1177-1182A new neuromuscular blocking azasteroid 4 having acetylcholine-like moiety in ring-A has been synthesised. An exploratory work to introduce the acetylcholine like fragment has been carried out in androstane series. After accomplishing the job, the target compound 4 has been synthesised starting from 4-hydroxy-17a-methyl-17a-aza-D-homo-4-androsten-3-one 12. An alternative route has also been adopted. The target compound 4 is found to be half as active as candocuronium 1 on weight basis on rat gastrocnemius sciatic muscle-nerve preparation

Peptidomimetic 2-cyanopyrrolidines as potent selective cathepsin L inhibitors

Cathepsins have been found to have important physiological roles. The implication of cathepsin L in various types of cancers is well established. In a search for selective cathepsin L inhibitors as anticancer agents, a series of 2-cyanoprrolidine peptidomimetics, carrying a nitrile group as warhead, were designed. Two series of compounds, one with a benzyl moiety and a second with an isobutyl moiety at P(2) position of the enzyme were synthesized. The synthesized compounds were evaluated for inhibitory activity against human cathepsin L and cathepsin B. Although, none of the compounds showed promising inhibitory activity, (E)N-{(S)1-[(S)2-cyano-1-pyrrolidinecarbonyl]-3-methylbutyl}-2,3-diphenylacrylamide (24) with an isobutyl moiety at P(2) was found to show selectivity as a cathepsin L inhibitor (Ki 5.3 muM for cathepsin L and Ki > 100 muM for cathepsin B). This compound could act as a new lead for the further development of improved inhibitors within this inhibitor type.Peer reviewed: YesNRC publication: Ye

Room-Temperature Ionic Liquid–DMSO Promoted and Improved One-Pot Synthesis of 5,6-Diaryl-1,2,4-triazines

<div><p></p><p>An improved and rapid one-pot synthesis of 5,6-diarylsubstituted-1,2,4-triazines in a mixture of room-temperature ionic liquid 1,3-dibutylimidazolium bromide [Bbim]⁺Br⁻ and dimethylsulfoxide (DMSO) is described without the need for any added catalyst. Different polar aprotic solvents were screened along with ionic liquids and a synergistic effect with DMSO has been found. The predominance of one regioisomer over the other has also been studied with varying reaction temperatures. The one-pot methodology leading to excellent isolated yields in short span of time is achieved by simple workup procedure. The ionic liquid was efficiently recovered and reused three times without the loss of catalysis. All the compounds were characterized by infrared, NMR, mass spectrometry, and elemental analysis.</p> </div

Novel 2‑Aminobenzamides as Potential Orally Active Antithrombotic Agents

In an effort to develop potent antithrombotic agents, a series of novel 2-aminobenzamide derivatives were synthesized and screened for their in vivo antithrombotic activity. Among the 23 compounds tested, compound (<b>8g</b>) showed the most promising antithrombotic activity, which was comparable with clinically used aspirin or warfarin, but at variance with these standard drugs, <b>8g</b> did not exhibit the increased bleeding time, suggesting its potential as a novel antithrombotic agent