Benzimidazoles, inhibitors

Substituted benzimidazole inhibitors show slightly different effects depending on the inhibitor structure. Omeprazole binds to cysteines in the extracytoplasmic regions of M5/M6 (cys-813) and M7/M8 (cys-892). 

Ishidaa, T., Suzuki, T., Hirashimaa, S., Mizutani, K., Yoshida, A., Ando, I., Ikeda, S., Adachi, T., Hashimoto, H. Benzimidazole inhibitors of hepatitis C virus NS5B polymerase identification of 2-[(4-diarylmethoxy)phenyl]-benzimidazole. Bioorg. Med. Chem. Lett. 2006, 36, 1859-1863. 

The membrane-bound H-1-/K-1- ATPase enzyme exchanges H-i- and K-i- ions, resulting in a four million-fold gradient in [H-i-], between a cytosolic pH of 7.3 and an intraluminal pH of 0.8. Benzimidazole inhibitors, such as omeprazole, lansoprazole, and pantoprazole, bind covalently and irreversibly with the enzyme. 

White AW, Almassy R, Calvert AH et al. Resistance-modifying agents. 9. Synthesis and biological properties of benzimidazole inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase. J Med Chem 2000 43 4084-4097. 

The pharmacotherapy of allergy and asthma has traditionally focused on the effecter molecules of the allergic cascade. They identified [91] and extended a novel family of 2-(substituted phenyl)benzimidazole inhibitors. Pharmacological activity depends on an intact phenylbenzimidazole-bis-amide backbone, and is optimized by the presence of lipophilic terminal groups 144. The broad profile of these compounds thus underscores their potential for treating the multifarious pathology of asthma. 

A large number of a-hydroxybenzylbenzimidazole [50-97-5] (HBB, 39), C24H22N2O, derivatives has been prepared and extensively studied as selective inhibitors of the RNA containing enterovimses (91). Although none of these derivatives have shown any antiviral activity in animals, l,2-bis(5-methoxy-2-benzimidazol-2-yl)-l,2-ethanediol [16656-27-2] (40), C2gH2gN404, was found to be active against an experimentally induced rhino vims infection in chimpanzees (92). However, the in vivo antiviral efficacy was accompanied by significant toxicity. 

A derivative of 163, 3-(2-morpholinoethylthio)[l,2,4]triazino[5,6-fo]indole dihydrochloride, is used as a thrombolytic (91URP1672373). Derivatives of the pyrazolo[5,l-c][l, 2,4]tria-zines were used as a constituent of silver halide color photographic supported material, which showed good color reproducibility [91JAP(K)03/291649]. The protective action of [l,2,4]triazino[4,3-a]benzimidazoles as corrosion inhibitors was studied (91MI8). 

The first compound of this class with inhibitory activity on the enzyme and on acid secretion was the 2-(pyridylmethyl)sulfinylbenzimidazole, timopra-zole, and the fust pump inhibitor used clinically was omeprazole, 2-[[3,5-dimethyl-4-methoxypyridin-2-yl] methylsulfinyl]-5-methoxy- lH-benzimidazole. Omeprazole is an acid-activated prodrug. Omeprazole and the other PPIs are accumulated in the acidic space of the parietal cell due to the pKa of the pyridine nitrogen and these are converted due to protonation of the benzimidazole nitrogen first to a thiol-reactive cationic sulfenic acid and then dehydrated to form the sulfenamide (Fig. 1). These thiophilic cations then bind to luminally... 

In this chapter, an attempt has been made to present a total number of 20 QSAR models (12 QSAR models for topo I inhibitors and eight QSAR models for topo II inhibitors) on 11 different heterocyclic compound series (an-thrapyrazoles, benzimidazoles, benzonaphthofurandiones, camptothecins, desoxypodophyllotoxins, isoaurostatins, naphthyridinones, phenanthridines, quinolines, quinolones, and terpenes) as well as on some miscellaneous heterocyclic compounds for their inhibition against topo I and II. They have been found to be well-correlated with a number of physicochemical and structural parameters. The conclusion, from the analysis of these 20 QSAR, has been drawn that the inhibition of topo I is largely dependent on the hydrophobicity of the compounds/substituents. On the other hand, steric parameters (molar refractivity, molar volume, and Verloop s sterimol parameters) are important for topo II inhibition. 

Other patent reports covering PDF inhibitors from structural classes different from those discussed above include hydrazides (43) [118], aryl-substituted pyrrolidines (44) [119], benzimidazoles (45, 46) [120-121], hydantoins (47) [122] and oxo-pyrrolidines (48) [123], A prodrug approach utilising PDF has been published by Pei, and patents have been published by NewBiotics, but in this case the compounds of interest are used as substrates rather than inhibitors (49) [124-126]. 

The Boger group [64-66] has extensively studied the use of a-ketoheterocycles as FAAH inhibitors. In their initial studies, a range of a-ketoheterocycles based on oleic acid was synthesised. A range of five- and six-membered monocyclic heterocycles and three bicyclic heterocycles (benzothiazole, benzimidazole and benzoxazole) was examined. Although many of the compounds tested were found to inhibit FAAH activity with micromolar affinities, the best results were obtained with heterocycles that incorporated a weakly basic nitrogen a - to the heterocycle (Table 6.5) [64]. 

A group of benzimidazole-2-pyrazole PHD2 inhibitors appeared in a recent patent application, with IC50 values as low as 16 nM for compound 43 in a [14C]-based enzymatic assay [64]. Furthermore, members of this class of compounds were reported to stimulate erythropoietin secretion from PIep3B cells by up to 150% at 100 pM concentrations. 

Potent IRAK-4 inhibitors have been reported by several groups including some structurally related benzimidazoles (e.g., 34-36) as well as alternative fused heterocycles such as the imidazopyridine (37) and imidazopyridazine (38) [102-107]. Such compounds are... 

A large number of patent applications has been filed, most recently describing imidazothiazoles [70], oxazolopyridines [71], benzimidazoles [72], benzothiazoles [73] and imidazopyridines [74] as sirtuin modulators, however it is not yet possible to determine which compound classes will prove most promising. Overall, due to their potential applications as new drug candidates for various indications, the class III HDAC inhibitors are currently a rapidly growing field of interest. 

Benzimidazole is an important heterocyclic nucleus in the field of medicinal chemistry. The most prominent benzimidazole compound in nature is N-ribosyldimethylbenzimidazole, which serves as an axial ligand for cobalt in vitamin B12. The versatile nature of benzimidazole makes it a highly explored molecule in medicinal chemistry. A number of pharmacological activities are associated with benzimidazole derivatives such as anthelmintic, antiulcer, antipsychotic, proton pump inhibitor, antianxiety, anti-emetic and sedative, vasodilator, anticancer, analgesic, antihistaminic, antifungal, antiviral and antimicrobial. 

Spotts, R. A., F. L. Lukezic, and N. L. Lacasse. The effect of benzimidazole, cholesterol, and a steroid inhibitor on leaf sterols and ozone resistance of bean. Phytopathology 65 45-49, 1975. 

GlaxoSmithKline has filed patent applications covering 5-(benzimidazol-l-yl)thiophenes 111 and 112 and 2-(benzimidazol-l-yl)thioazoles 113 as inhibitors of PLK-1 [274,275]. Many potent compounds were claimed for 5-(benzimidazol-l-yl)thiophene series, including analog 111 with submicromolar inhibition against PLK-1 and anti-proliferative activity in five out of the six tumor cell lines tested. According to the data disclosed in the filing, a variety of substituents were accommodated on the 5- and 6-positions of the ben-... 

Omeprazole is an antiulcer drug. It is a proton pump inhibitor. This substituted benzimidazole inhibits gastric acid secretion to help acid/peptic disorders and duodenal ulcers. It interferes with the proton pump in the mucous lining of the stomach, the last stage of acid production. It can turn off stomach acid in as little as one hour. Lansoprazole (no. 12) has a similar structure. 

Astemizole, mizolastine, tecastemizole, and levocastatine are selective Hi histamine inhibitors indicated particularly for allergic rhinitis (Figure 8.48). They have few or even no sedative effects. Indeed, the effects are mainly peripheral since these compounds do not easily cross through the blood-brain barrier. Astemizole, mizolastine, and tecastemizole contain the same A - -fluorobenzyl benzimidazole moiety. 

Rabeprazole belongs to substituted benzimidazole proton-pump inhibitors. In gastric parietal cells, rabeprazole is proto-nated, accumulates and is transformed to an active sulfenamide. 

Five proton pump inhibitors are available for clinical use omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole. All are substituted benzimidazoles that resemble H 2 antagonists in structure (Figure 62-3) but have a completely different mechanism of action. Omeprazole is a racemic mixture of R- and S-isomers. Esomeprazole is the S-isomer of omeprazole. All are available in oral formulations. Esomeprazole and pantoprazole are also available in intravenous formulations (Table 62-2). 

The Design and biological profile of angiotensin-converting enzyme inhibitors, 23, 161 Design of new drugs for helminth diseases Lead optimization in benzimidazoles, 25, 103 Design and therapeutic potential of peptides, 21, 145... 

Okumura, Y., Murata, Y., Mano, T. Benzimidazole derivatives as cyclooxygenase-2 inhibitors (Pfizer Inc.), EP-0937722,1999. 

Microtubulin Polymerization Inhibitors. The benzimidazoles were first reported to have systemic fungicidal activity in 1964 (29). 

Well over 100 plant pathogens have become resistant to various fungicides under field conditions. Failure of the acyl alanines, benzimidazoles, thiophanates, carboxanilides, dicarboximides, hydroxypyrimidines, some organophosphates, and most of the antibiotics has occurred. In other cases, a moderate decrease in sensitivity without a rapid loss of disease control has been observed as in the case of sterol biosynthesis inhibitors (triazoles, pyrimidines, and imidazoles) and organophosphates. The most effective approach is to use fungicides having different modes of action in combination,... 

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