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

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

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

Design, green synthesis and pharmacological evaluation of novel 5,6-diaryl-1,2,4-triazines bearing 3-morpholinoethylamine moiety as potential antithrombotic agents^*

<p>The aim of this research work was to investigate a series of novel 5,6-diaryl-1,2,4-triazines (<b>3a</b>–<b>3q</b>) containing 3-morpholinoethylamine side chain, and to address their antiplatelet activity by <i>in vitro, ex vivo</i> and <i>in vivo</i> methods. All compounds were synthesized by environment benign route and their structures were unambiguously confirmed by spectral data. Compounds (<b>3l</b>) and (<b>3m</b>) were confirmed by their single crystal X-ray structures. Out of all the synthesized compounds, 10 were found to be more potent <i>in vitro</i> than aspirin; six of them were found to be prominent in <i>ex vivo</i> assays and one compound (<b>3d</b>) was found to have the most promising antithrombotic profile <i>in vivo</i>. Moreover, compound (<b>3d</b>) demonstrated less ulcerogenicity in rats as compared to aspirin. The selectivity of the most promising compound (<b>3d</b>) for COX-1 and COX-2 enzymes was determined with the help of molecular docking studies and the results were correlated with the biological activity.</p

Overview of the Development of DprE1 Inhibitors for Combating the Menace of Tuberculosis

Decaprenylphosphoryl-β-d-ribose 2′-epimerase (DprE1), a vital enzyme for cell wall synthesis, plays a crucial role in the formation of lipoarabinomannan and arabinogalactan. It was first reported as a druggable target on the basis of inhibitors discovered in high throughput screening of a drug library. Since then, inhibitors with different types of chemical scaffolds have been reported for their activity against this enzyme. Formation of a covalent or noncovalent bond by the interacting ligand with the enzyme causes loss of its catalytic activity which ultimately leads to the death of the mycobacterium. This Perspective describes various DprE1 inhibitors as anti-TB agents reported to date