Syntheses and Selective Inhibitory Activities of Terphenyl‐Bisamidines for Serine Proteases

Abstract

Biphenyl nitriles 5a-c, terphenyl dinitriles 11a-d, and naphthalene-bis(benzonitrile) 11c were prepared by palladium-catalyzed cross coupling reactions and subsequently converted to biphenyl amidines 8a-c and bis(benzamidines) 4a-e. Among the biphenyl amidines 8 only the meta-derivative 8b inhibits factor Xa and trypsin (Ki = 10 microM). The terphenyl bisamidine 4c does not inhibit factor Xa, trypsin, thrombin, and plasmin, while 4a and 4d are almost equipotent inhibitors of these enzymes (Ki 1-6 microM), and 4b and 4e are selective for trypsin (Ki = 0.2 and 0.3 microM; but Ki > 1 microM for factor Xa, thrombin, and plasmin). X-ray analysis of crystals of 4b complexed with bovine trypsin revealed a unique binding mode: one benzamidino group binds in the S1 site to the side chain carboxylate of Arg189. The central phenyl group is twisted away from the S2/S3 sites and the second amidino group contacts the Asn143 side chain.

Structure-directed discovery of potent non-peptidic inhibitors of human urokinase that access a novel binding subsite

“…The S 1β pocket is a shallow subsite that has not been widely used for structure-based drug design of other serine protease inhibitors. One inhibitor, terphenylbisamidine, has been shown to access S 1β in trypsin and to hydrogen bond with Asn143 [46]. Because urokinase has a lysine at position 143, however, this inhibitor's substituent would probably interact unfavorably at the S 1β site of urokinase.…”

Synthesis and Applications of Group 14-metalated Arylboranes

“…The Sn C bond in 28 reacted also with 4-bromobenzonitrile to give a boronated cyanobiphenyl 118 in 48% yield. 118 was subsequently converted into a terphenyl 119 by the Suzuki coupling with 3-bromobenzonitrile (Scheme 51) [118]. …”

Synthesis of N -substituted aryl amidines by strong base activation of amines

“…Its derivatives act as antimicrobial and antiparasitic agents and have been used for the treatment of a variety of diseases, including pneumocystis pneumonia, antimonyresistant leishmaniasis, and human African trypanosomiasis. 14–20 Amidines are known to bind nucleic acids; such action is crucial to their mechanism of action in some disease models. 21–24 This property has been known for some time, and modulation of long, amidine-containing compounds has been proposed for sequence-specific targeting of both RNA and DNA.…”