Diarylamidine derivatives with one or both of the aryl moieties consisting of an indole or indole-like ring. Inhibitors of arginine-specific esteroproteases

Abstract

A series of 62 diarylamidine derivatives was evaluated for their antiproteolytic activity. In all but two of the compounds one or both of the amidino-substituted aryl moieties was either an indole or an indole-like ring. The latter included indene, benzimidazole, benzofuran, benzol[beta]thiophene, and several other related nitrogen-containing heterocycles. Several of the compounds exhibited considerable inhibitory potency against thrombin, trypsin, and pancreatic kallikrein. An outstanding inhibitor of trypsin was found in bis(5-amidino-2-benzimidazolyl)methane (compound 42) with a Ki value of 1.7 X 10(-8) M(pH. 8.1, 37 degrees C). Another derivative, 1,2-di(4-amidino-2-benzofuranyl)ethane (compound 21), proved to be a highly effective inhibitor of the overall blood clotting process. From a general structure-activity standpoint these compounds demonstrate that minor structural variations of low-molecular-weight inhibitors can result in significant changes in specificity and potency with regard to antiproteolytic activity.

Novel Broad-Spectrum Bis-(Imidazolinylindole) Derivatives with Potent Antibacterial Activities against Antibiotic-Resistant Strains

“…This class of compounds has been evaluated previously for antimicrobial properties (2), as well as for antiproteolytic, anticoagulant (23), and antiproliferative activity (5). In our study, four bis-(imidazolinylindole) compounds from the diarylamidine library exhibited very potent activity in the macrophage rescue screen.…”

Protease inhibitors suppress the in vitro and in vivo replication of rotavirus.

“…The following protease inhibitors were obtained from Sigma Chemical Co., St. Louis, MO or Peninsula Laboratories, Santa Clara, CA: soybean trypsin inhibitor, human alpha-l-antitrypsin, antipain, bestatin, leupeptin, and chymostatin. Pentamidine and BABIM were synthesized according to previously described methods (28,29).…”

“…It is believed that the same process occurs in the small intestine, where a high level of protease activity exists and which is the principal site of rotaviral replication. Recently, a number of low-molecular weight aromatic diamidines that are potent inhibitors of trypsin-like proteases have been synthesized (28,29). One of these compounds, bis (5-amidino-2-benzimidazolyl) methane (BABIM),' is the most potent synthetic, reversible inhibitor of trypsin yet identified.…”

Synthesis and Molecular Docking for Antiinflammatory Studies of 2-(Arylmethyl)-1-ethyl-1H-benzo[d]imidazol-5-amines

“…Likewise, the common preparation of these compounds is by the condensation reaction of 1,2-phenylenediamine with carboxylic acids, carboxaldehydes [6,7], or their derivatives [8,9] such as, nitriles, chlorides and ortho-esters under strong acidic conditions. These have also been synthesized by combinatorial and solid phase approach [10,11].…”