In Vitro Structure−Activity Relationship and in Vivo Studies for a Novel Class of Cyclooxygenase-2 Inhibitors:  5-Aryl-2,2-dialkyl-4-phenyl-3(2H)furanone Derivatives

Abstract

5-Aryl-2,2-dialkyl-4-phenyl-3(2H)furanone derivatives were studied as a novel class of selective cyclooxygenase-2 inhibitors with regard to synthesis, in vitro SAR, antiinflammatory activities, pharmacokinetic considerations, and gastric safety. 1f, a representative compound for methyl sulfone derivatives, showed a COX-2 IC(50) comparable to that of rofecoxib. In case of 20b, a representative compound for sulfonamide derivatives, a potent antiinflammatory ED(50) of 0.1 mg kg(-1) day(-1) was observed against adjuvant-induced arthritis by a preventive model, positioning 20b as one of the most potent COX-2 inhibitors ever reported. Furthermore, 20b showed strong analgesic activity as indicated by its ED(50) of 0.25 mg/kg against carrageenan-induced thermal hyperalgesia in the Sprague-Dawley rat. 3(2H)Furanone derivatives showed due gastric safety profiles as selective COX-2 inhibitors upon 7-day repeat dosing. A highly potent COX-2 inhibitor of the 3(2H)furanone scaffold could be considered suitable for a future generation COX-2 selective arthritis medication with improved safety profiles.

Pt-catalyzed cyclization/migration of propargylic alcohols for the synthesis of 3(2H)-furanones, pyrrolones, indolizines, and indolizinones

“…The 3(2H)-furanones are a class of important heterocycles that are found in a variety of biologically active natural products such as the eremantholides 1 and jatrophone 2 as well as several medicinally active agents. 3 Various methods have been developed for the synthesis of these heterocycles, including the conversion of 3-alkoxy-furans to 2-alkoxy furanones 4 and the reaction of 3-silyloxyfurans with electrophiles 5 such as aldehydes. Most of the current approaches to furanones remain rather specialized or demand considerable investment in the preparation of the requisite precursor substrates.…”

Synthesis of a new class of antimicrobial agents incorporating the indolin-2-one moiety

“…(3 a-l ) were established on the basis of IR, mass spectrum, 1 HNMR, and 13 CNMR spectral data. The IR spectra of compounds (3 g-l ) revealed absorption bands at 3,425-3,397 (NH), while compounds (3a-f) displayed no frequencies for a NH group.…”

“…The structures of (4 a-e ) were established Scheme 1. Synthesis of the target compound 3. from IR, mass, 1 HNMR, and 13 CNMR spectra. The 1 HNMR spectra of compounds (4 a-e ) displayed the NH protons of the NH 2 group which disappeared on addition of D 2 O. Cyclization of 2-[(5-Alkyl-2-oxoindolin-3-ylidene)-4-oxo-4-(4-alkylphenyl)]butane hydrazides (4 a-e ) can occurred with microwave irradiation in ethanol to give 5-alkyl-3-[(oxo-6-(4-alkylphenyl)-2,3-dihydropyridazin-4-(5H)-ylidene)]indolin-2-ones (5 a-d ).The structures of the products were confirmed by IR, mass, 1 HNMR, and 13 CNMR spectra.…”

“…Since various kinases are involved in the growth of microorganisms and because many oxindoles are kinase inhibitors 6,[12][13][14][15][16] , a variety of 3-substituted indolin-2-ones have been utilized as anticancer drugs or drug candidates [17][18][19][20][21] . A representative member of this class is Sunitinib (SU11248, SutentTM; Pfizer, Cairo, Egypt) which is currently used in the clinics as a multi-targeting tyrosine kinase inhibitor with antiangiogenic activity Figure 1 22,23 .…”

Design, synthesis, andIn vitroantituberculosis activity of 2(5H)-Furanone derivatives

“…In particular, compounds bearing the 2-furanone backbone have exhibited diverse biological activities, such as antiprotozoal, antibacterial (including inhibition of biofilm formation), antimycobacterial, antitumoral, antifungal, and cyclooxygenase-2 inhibition (8)(9)(10)(11)(12)(13)(14). The efficacy of several butyrolactone derivatives against mycobacteria suggests that these structures be a new template for tuberculosis drug development (14,15).…”