Synthesis and pharmacological evaluation of m-terphenyl amines as cyclooxygenase inhibitors

Abstract

A series of m-terphenyl amines was synthesized and evaluated as a novel class of cyclooxygenase (COX) inhibitors. Structure-activity relationships (SAR) were investigated by functional group modification at the para-position of the C-1 0 and C-2 0 phenyl substituents on the central aromatic ring. Anilines 6a, b, d, and h demonstrated nonselective inhibition of COX-1 and -2 in human whole blood. Compounds 6c and e demonstrated preferential inhibition of the COX-2 isozyme at 10 lM. Molecules 6f, i, and j inhibited only COX-1, and the disubstituted ethoxy derivative (6g) was inactive as a COX inhibitor ( 100 lM). Molecular docking studies of these compounds indicate that the COX-1 binding site amino acid Ile 523 anchors the m-terphenyl system statically within the enzyme's active site, while the slightly smaller amino acid Val 523 in COX-2 allows the ligand to ''roll,'' fashioning several acceptable conformers.

2,6-Dicyanoaniline based donor-acceptor compounds: the facile synthesis of fluorescent 3,5-diaryl/hetaryl-2,6-dicyanoanilines

“…Conventionally, the syntheses of 3,5-disubstituted-2,6-dicyanoanilines are catalyzed by a basic catalyst such as piperidine. 18,19 Many other homogeneous and heterogeneous catalysts instead of piperidine were also employed for this coupling, including NaOH, solvent free molten K 2 CO 3 , ethanediamine, NaOH/ZnTiO 3 and KF/Alumina [20][21][22][23] . Moreover, they were also prepared under microwave irradiation and by different methods of grinding.…”

Design and synthesis of 3-[3-(substituted phenyl)-4-piperidin-1-ylmethyl/-4-morpholin-4-ylmethyl-4,5-dihydro-isoxazol-5-yl]-1H-indoles as potent anti-inflammatory agents

“…Moreover, isoxazoline derivatives have been reported to possess potent protein tyrosine phosphatase inhibitor, and anti-inflammatory activity (Basappa et al, 2004;Habeeb et al, 2001;Maurya et al, 2008). Recently, m-terphenyl amines, which do not have traditional arylacetic acid moiety, have been reported to possess potent cyclooxygenase-inhibiting activity (Bauer et al, 2007). Encouraged by these observations and also in continuation of our search for potent anti-inflammatory molecules (Amir et al,.…”

Synthesis of Terphenyls

“…105 The construction of flanking aryl groups may also be achieved by the reaction of arylidenemalonodinitriles 22 and ethyl dicyanomethylenepropanoate 23 (generated from ethyl pyruvate and malononitrile), but in much lower yields (Scheme 32, equation 2). 106 A few modifications of this reaction were reported, including the reaction between chalcones and malononitriles (Scheme 32, equation 3), 107 or the reaction of vinyl malonodinitriles (obtained by Knoevenagel reactions) with nitroolefins via one-pot tandem addition processes (Scheme 32, equation 4).…”