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

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

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

Metaloantibiotici: Sinteza, karakterizacija i antimikrobno djelovanje kompleksa fluorokinolona s bizmutom na Helicobacter pylori

Novel organometallic compounds have been prepared by complexing the fluoroquinolones, norfloxacin, ofloxacin, ciprofloxacin, sparfloxacin, lomefloxacin, pefloxacin and gatifloxacin, with bismuth. The complexes were characterized by UV, IR, atomic absorption spectroscopy, elemental analysis, differential scanning calorimetry, thermogravimetric analysis and mass spectrometry. Their antibacterial potential against Helicobacter pylori and other microorganisms was investigated. These compounds were found to possess strong activity against Helicobacter pylori at a minimum inhibitory concentration of 0.5 mg Ll. They also exhibited moderate activity against Escherichia coli, Staphylococcus aureus, Bacillus pumilus and Staphylococcus epidermidis. These bismuth-fluoroquinolone complexes have the potential to be developed as drugs against H. pylori related ailments.Komplesacijom fluorokinolona, norfloksacina, ofloksacina, ciprofloksacina, sparfloksacina, lomefloksacina, pefloksacina i gatifloksacina s bizmutom pripravljeni su novi organometalni spojevi. Dobiveni kompleksi karakterizirani su UV, IR i atomskom apsorpcijskom spektroskopijom, elementarnom analizom, diferencijalnom pretražnom kalorimetrijom, termogravimetrijskom analizom i spektrometrijom masa. Nadalje, ispitivan je njihov učinak na Helicobacter pylori i druge mikroorganizme. Ispitivani spojevi pokazuju snažno djelovanje na Helicobacter pylori u koncentraciji 0,5 mg Ll te umjereno djelovanje na Escherichia coli, Staphylococcus aureus, Bacillus pumilus i Staphylococcus epidermidis. Kompleksi fluorokinolona s bizmutom potencijalni su lijekovi za infekcije uzrokovane H. pylori