Structure−Activity Relationship of 2-[[(2-Pyridyl)methyl]thio]-1H- benzimidazoles as AntiHelicobacter pyloriAgents in Vitro and Evaluation of their in Vivo Efficacy

Abstract

A relationship between the structure of 21 2-[[(2-pyridyl)methyl]thio]-1H-benzimidazoles (6) and their anti Helicobacter pylori activity expressed as minimum bactericidal concentration (MBC) values is described. Observed MBCs ranged from 256 to 1 microg/mL. The structure-activity relationship (SAR) showed that larger and more lipophilic compounds, especially compounds with such substituents in the 4-position of the pyridyl moiety, generally had lower MBC values. Four new compounds that were predicted to be potent by the established SAR model were synthesized and tested. One such compound, i.e., 2-[[(4-[(cyclopropylmethyl)oxy]-3-methyl-2-pyridyl)methyl]thio]-1H-be nzimidazole (18), was tested for in vivo efficacy in a mouse Helicobacter felismodel (125 micromol/kg bid given orally for 4 days, n = 4). Unfortunately, antibacterial activity could not be clearly demonstrated in this model. Instead a potent acid secretion inhibition was observed. This finding was attributed to the methylthio compound being oxidized to the corresponding methyl sulfinyl derivative, i.e., a proton pump inhibitor, in vivo. Although the antibacterial activity had the potential of decreasing H. felis cell counts in vivo the proton pump inhibitory effect became dominant and actually promoted H. felis cell growth. Hence, we conclude that the antibacterial utility of the 2-[[(2-pyridyl)methyl]thio]-1H-benzimidazoles (6) as a compound class is compromised by their propensity to become proton pump inhibitors upon metabolic oxidation in vivo.

Synthesis and Biological Evaluation of Novel Benzimidazole Derivatives Bearing a Heterocyclic Ring at 4/5 Position

“…1 Benzimidazole derivatives are structural isosteres of naturally occurring nucleotides, which allows them to interact easily with the biopolymers of the living systems. Therefore, benzimidazole derivatives have shown different therapeutic properties such as antiulcer, 2 antihelminthic, 3 antihypertensive, 4 anticoagulant, 5 antiallergic, 6 analgesic, 7 anti-inflammatory, 8 antimicrobial, 9 antiviral, 10 antiparasitic, 11 and antioxidant.…”

Facile Access to Benzothiazole‐Containing Pyrrolo[1,2‐a]quinolines and Pyrrolo[2,1‐a]isoquinolines via Nitrogen Ylides

“…[10][11][12][13] In addition, benzothiazoles are highly versatile chemicals which exhibit a wide spectrum of use in pharmaceutical and industrial areas. [14][15][16][17] The use of heteroaromatic N-ylides as 1,3-dipoles has received increasing interest in the synthesis of new condensed heterocyclic structures via 3+2 cycloaddition. [18][19][20][21] As part of our research interest towards developing new routes for the synthesis of quinoline and isoquinoline heterocycles, [22][23][24][25][26] we report here a novel route to some new benzothiazole-containing pyrrolo [1,2-a]quinolines and pyrrolo [2,1-a]isoquinolines utilizing versatile quinolinium and isoquinolinium N-ylides.…”

Synthesis and Biological Activity of N-Substituted-3-chloro-2-azetidinones

“…They also function as enzyme inhibitors and are effective on the central nervous system [12]. 2-Aminobenzothiazoles constitute another class of heterocycles that possess antimicrobial and various other pharmacological activities like diuretic, antiulcer, antihistamine and anticancer properties [13][14][15][16].…”