Pharmacological Properties of 2-Aminobenzimidazole Halides and Imidazo[1,2-a]Benzimidazole Derivatives

Russian Journal of Bioorganic Chemistry - Halides of 2-aminobenzimidazolium and derivatives of 9-substituted 2-(4-fluorophenyl)imidazo[1,2-a]benzimidazoles have been studied for ten types of...     

Quinolizidinyl-benzimidazoles as platelet-antiaggregating agents

Two series of (+/-)-2-phenyl-1-(quinolizidin-1 alpha-yl)benzimidazoles, 12A-26A, and (+/-)-2-phenyl-1-(quinolizidin-1 beta-yl)benzimidazoles, 12B-26B, were prepared and tested for the inhibition of human platelets aggregation induced by ADP, collagen, and adrenaline. All epimers A, i.e., 12A-26A, were devoid of any activity against the three agonists, while the epimers B, i.e., 12B-26B, exhibited different degrees of activity, though practically confined against the ADP-induced aggregation. The best compounds were 19B, 24B, and 26B, which inhibited for 69-67% at 260 microM and for 40-29% at 65 microM concentration the ADP (2 microM)-induced aggregation. The observed agonist and spatial structure selectivity warrant further investigations of this kind of benzimidazole derivatives.     

Polyhalogenobenzimidazoles: synthesis and their inhibitory activity against casein kinases

A series of novel polyhalogenated benzimidazoles have been prepared by exhaustive bromination of a variety of 2-substituted benzimidazoles. The efficacy of both new compounds and a number of their previously described cognates as inhibitors of casein kinases CK1, CK2 and G-CK was investigated. The type of N-1 alkyl substituent as well as introduction of a polyfluoroalkyl moiety at position 2 did not markedly influence the inhibitory efficacy toward CK2 of the respective 4,5,6,7-tetrabromobenzimidazole derivatives which conversely were almost ineffective toward CK1 and G-CK. However, 4,5,6,7-tetrabromobenzimidazoles substituted at position 2 with either chlorine, bromine or sulfur atom, while manifesting a still considerable inhibitory activity against CK2 (IC(50) in the 0.49-0.93 microM range) proved to be potentially powerful inhibitors also against CK1 (IC(50) in the 18.4-2.2 microM range).     

Synthesis and characterization of a potent and selective protein tyrosine phosphatase inhibitor, 2

The synthesis and biological activity of a series of 2-[(4-methylthiopyridin-2-yl)methylsulfinyl]benzimidazoles are described. These compounds have potent inhibitory effects against the protein tyrosine phosphatase activity of CD45. Enzymatic analysis with several phosphatases revealed that compound 5a had high specificity for CD45 compared with serine/threonine phosphatases (PP1, PP2A), tyrosine phosphatases (LAR, PTP1B and PTP-S2) and dual phosphatase (VHR).     

Synthesis and inhibitory activity of new benzimidazole derivatives against Burkitt's lymphoma promotion

As a continuation to our previous work concerning antitumor benzimidazoles, we have synthesized series of new derivatives of 2-(1-benzyl-2-methyl-1H-benzimidazol-5-ylimino)-3-(substituted)-thiazolidin-4-one (6a-e), 3-(2-methyl-1H-benzimidazol-5-yl)-2-substituted-thiazolidin-4-one (9a-f) and we have studied their inhibitory activity against the Epstein-Barr virus-early antigen (EBV-EA) activation introduced by 12-O-tetradecanoylphorbol-13-acetate (TPA). Compound 6d was found to be significantly active and compounds 5a and 6e were also active.     

A QSAR study on some series of anti-hepatitis B virus (HBV) agents

A quantitative structure-activity relationship (QSAR) study has been made on some series of anti-hepatitis B virus (HBV) agents, namely, a series of novel bis(L-amino acid) ester prodrugs of 9-[2--(phosphonomethoxy)ethyl]adenine, a similar series of compounds comprising of 2- amino-6-arylthio-9-[2-(phosphonoethoxy)ethyl] purine bis(2,2,2- trifluoroethyl) esters, and a series of 1-isopropylsulfonyl-2-amine benzimidazoles. In each case significant correlations are found between the anti-HBV potencies and some physicochemical and steric properties of the compounds, indicating that for the first two series the activity is controlled by the hydrophobic and the bulk properties of the molecules and, for the third series, the steric and hydrogen bonding properties of compounds are crucial for their anti-HBV potency.     

Benzimidazole derivatives endowed with potent antileishmanial activity

Two sets of benzimidazole derivatives were synthesised and tested in vitro for activity against promastigotes of Leishmania tropica and L. infantum. Most of the tested compounds resulted active against both Leishmania species, with IC₅₀ values in the low micromolar/sub-micromolar range. Among the set of 2-(long chain)alkyl benzimidazoles, whose heterocyclic head was quaternised, compound 8 resulted about 100-/200-fold more potent than miltefosine, even if the selectivity index (SI) versus HMEC-1 cells was only moderately improved. In the set of 2-benzyl and 2-phenyl benzimidazoles, bearing a basic side chain in position 1, compound 28 (2-(4-chlorobenzyl)-1-lupinyl-5-trifluoromethylbenzimidazole) was 12-/7-fold more potent than miltefosine, but exhibited a further improved SI. Therefore, compounds 8 and 28 represent interesting hit compounds, susceptible of structural modification to improve their safety profiles.     

A study on the antioxidant activities of some new benzazole derivatives

The in vitro antioxidant properties of some new benzazole derivatives (1-10) such as benzoxazoles, benzimidazoles, and benzothiazoles were determined by their effects on the rat liver microsomal NADPH-dependent lipid peroxidation (LP) level, the scavenging of superoxide anion and the stable radical 2,2-diphenyl-1-picrylhydrazyl (DPPH). Compounds 1, 2, 4 and 6, showed potent scavenging effect on superoxide radical at 10(-3) M. Compound 8, 5-nitro-2-(phenoxymethyl)benzimidazole, strongly inhibited lipid peroxidation at 10(-3) M concentration.     

Molecular docking and dynamic simulations of benzimidazoles with beta-tubulins

It is of interest to document the molecular docking and dynamic simulations of benzimidazoles with beta-tubulins in the context of anthelmintic activity. We document the compound BI-02 (2-(3,4-dimethyl phenyl)-1H-1,3-benzimidazole (BI-02) with optimal bindig features compared to the standard molecule albendazole (7.0 Kcal/mol) with binding energy -8.50 Kcal/mol and _PIC₅₀ value 583.62 nM.     

Effects of Insect-Growth-Regulatory Benzimidazole Derivatives on Cultured Integument of the Rice Stem Borer and Mitochondria from Rat Liver

The larvicidal activities of benzimidazole derivatives with a terpenoid side chain on the rice stem borer and the silkworm were compared with such in vitro activities as the growth inhibition of the cultured integument of the rice stem borer and the respiration inhibition of rat liver mitochondria. Each larvicidal activity is parallel with these in vitro activities. The comparisons of their activities with those of rotenone and diflubenzuron indicate that the benzimidazoles mainly acted as respiration inhibitors in their larvicidal activity as well as causing cuticular growth inhibition. The activity of 1-(3,7-dimethyl-7-ethoxy-2-octenyl)-2-methylbenzimidazole, the most potent compound tested as a respiration inhibitor, was found to be about 6-fold higher than that of rotenone. In the respiratory chain, the site between NADH and ubiquinone was blocked, indicating that the larvicidal benzimidazoles shared a mode of action with those of rotenone, piericidins, and ubicidines.     

2-(4,5-Dihydroimidazol-2-yl)benzimidazoles as highly selective imidazoline I2/adrenergic alpha2 receptor ligands

2-(4,5-Dihydroimidazol-2-yl)benzimidazoles have been identified as selective imidazoline I2/alpha2-adrenoceptor ligands. 4-Methyl (2) and 4-chloro (4) derivatives display I2 affinity at nanomolar concentration (Ki=4.4 and 17.7 nM, respectively) and high I2/alpha2 selectivity ratio=4226 and 5649, respectively. An evidence has been obtained that pKa value influences considerably the I2/alpha2-selectivity ratio of this class of imidazoline I2 receptor ligands.     

Inhibitory properties of 2-substituent-1H-benzimidazole-4-carboxamide derivatives against enteroviruses

A series of novel benzimidazole derivatives were designed, synthesized, and evaluated for their activities against four kinds of enteroviruses, that is, Coxsackie virus A16, B3, B6 and Enterovirus 71 in VERO cells. Strong activities against enterovirus replication and low cytotoxicities were observed in these benzimidazoles generally. The most promising compound was (l)-2-(pyridin-2-yl)-N-(2-(4-nitrophenyl)pentan-3-yl)-1H-benzimidazole-4-carboxamide (16), with a high antiviral potency (IC(50)=1.76 μg/mL) and a remarkable selectivity index (328). These compounds were selected for further evaluation as novel enterovirus inhibitors.     

Indapamide-like benzenesulfonamides as inhibitors of carbonic anhydrases I, II, VII, and XIII

A series of novel 2-chloro-5-[(1-benzimidazolyl- and 2-benzimidazolylsulfanyl)acetyl]benzene-sulfonamides were designed and synthesized. Their binding to recombinant human carbonic anhydrase (hCA) isozymes I, II, VII, and XIII was determined by isothermal titration calorimetry and thermal shift assay. The designed S-alkylated benzimidazole derivatives exhibited stronger binding than the indapamide-like N-alkylated benzimidazoles, with the K(d) reaching about 50-100 nM with drug-targeted hCAs VII and XIII. The cocrystal structures of selected compounds with hCA II were determined by X-ray crystallography, and structural features of the binding event were revealed.     

A single point mutation in the TRPC3 lipid-recognition window generates supersensitivity to benzimidazole channel activators

Mutation of a single residue within the recently identified lipid (diacylglycerol) recognition window of TRPC3 (G652A) was found to abolish channel activation via endogenous lipid mediators while retaining sensitivity to the non-lipid activator GSK1702934A (abb. GSK). The mechanism of this change in chemical sensing by TRPC3 was analysed by whole-cell and single channel electrophysiology as well as Ca²⁺ imaging. Currents initiated by GSK or the structural (benzimidazole) analog BI-2 were significantly larger in cells expressing the G652A mutant as compared to wild type (WT) channels. Whole cell patch-clamp experiments revealed that enhanced sensitivity to benzimidazoles was not due to augmented potency but reflected enhanced efficacy of benzimidazoles. Single channel analysis demonstrated that neither unitary conductance nor I-V characteristics were altered by the G652A mutation, precluding altered pore architecture as the basis of enhanced efficacy. These experiments uncovered a distinct gating pattern of BI-2-activated G652A mutant channels, featuring a unique, long-lived open state. Moreover, G652A mutant channels lacked PLC/diacylglycerol mediated cross-desensitization for GSK activation as typically observed for TRPC3. Lack of desensitization in G652A channels enabled large GSK/BI-2-induced Ca²⁺ signals in conditions that fully desensitized TRPC3 WT channels. We demonstrate that the lipid-recognition window of TRPC3 determines both sensitivity to lipid mediators and chemical gating by benzimidazoles. TRPC3 mutations within this lipid interaction site are suggested as a basis for chemogenetic targeting of TRPC3-signaling.     

Towards a systematic characterization of the antiprotozoal activity landscape of benzimidazole derivatives

Parasitic infections caused by the protozoa Trichomonas vaginalis and Giardia intestinalis still represent a major problem in developing countries. Despite the fact that benzimidazoles are promising compounds with activity against both protozoa, systematic studies to characterize and compare their structure-activity relationships (SAR) are limited. Herein, we report a systematic characterization of the SAR of 32 benzimidazoles with activity against T. vaginalis and G. intestinalis. The analysis was based on pairwise comparisons of the activity similarity and molecular similarity using different molecular representations. Radial, MACCS keys, TGD and piDAPH3 fingerprints were used to develop consensus models of the landscape. The landscapes contained continuous regions and activity cliffs. Two 'deep consensus activity cliffs' and several pairs of compounds in smooth regions of the SAR were identified in the landscape of T. vaginalis. In contrast, a number of 'apparent and shallow cliffs' were found for G. intestinalis. Several compounds active for both parasites showed similar SAR suggesting a common mechanism of action. We also identified pairs of structurally similar molecules with dramatic changes in selectivity. Results suggested that while substitution at position 2 on the benzimidazole moiety plays an important role in increasing the potency against both parasites, substitutions at positions 4-7 could influence selectivity. This study represents a first step towards the systematic characterization of the antiprotozoal activity landscape of benzimidazoles, and has direct implications in the future development of other types of quantitative models. The landscape of larger data sets with other biological endpoints can be analyzed using the general approaches used in this work.     

Synthesis,antiprotozoal and antibacterial activity of nitro- and halogeno-substituted benzimidazole derivatives

Two series of benzimidazole derivatives were sythesised. The first one was based on 5,6-dinitrobenzimidazole, the second one comprises 2-thioalkyl- and thioaryl-substituted modified benzimidazoles. Antibacterial and antiprotozoal activity of the newly obtained compounds was studied. Some thioalkyl derivatives showed remarkable activity against nosocomial strains of Stenotrophomonas malthophilia, and an activity comparable to that of metronidazole against gram-positive and gram-negative bacteria. Of the tested compounds, 5,6-dichloro-2-(4-nitrobenzylthio)-benzimidazole showed the most distinct antiprotozoal activity.     

Benzimidazoles as benzamide replacements within cyclohexane-based CC chemokine receptor 2 (CCR2) antagonists

We describe the design, synthesis, and evaluation of benzimidazoles as benzamide replacements within a series of trisubstituted cyclohexane CCR2 antagonists. 7-Trifluoromethylbenzimidazoles displayed potent binding and functional antagonism of CCR2 while being selective over CCR3. These benzimidazoles were also incorporated into lactam-containing antagonists, thus completely eliminating the customary bis-amide.     

Cu-Zn-superoxide dismutase activity in Moniezia expansa: inhibition by pyrimidine derivatives

Copper-zinc, cyanide-sensitive superoxide dismutase (Cu-Zn-SOD) was detected in homogenates of Moniezia expansa. The enzyme was purified by a sequence of multiple differential centrifugations, ammonium sulphate precipitation, ion-exchange and G-75 Sephadex column chromatography. The final enzyme preparation had a specific activity of 623.00 +/- 9.97U per mg protein and, after isolation, a single-staining band on acrylamide-SDS gels was detected which coincided with enzyme activity. The inhibitory activities of several benzimidazoles and several novel pyrimidine derivatives were determined on purified extracts of the M. expansa Cu-Zn-SOD. The results indicated that the percentage inhibition of Cu-Zn-SOD by some pyrimidine derivatives (6-amino-1, 3-dimethyl-5-nitroso-uracil, 6-amino-5-methyl-5-nitroso-uracil and 5-amino-uracil) was markedly higher than inhibition with the benzimidazoles.     

The synthesis and chemistry of certain anthelmintic benzimidazoles

A basis for interest in the benzimidazole ring system as a nucleus from which to develop potential chemotherapeutic agents was established in the 1950s when it was found that 5,6-dimethyl-l-(alpha-D-ribofuranosyl)benzimidazole (I) was an integral part of the [structure: see text] structure of vitamin B(12). As a result of these interests and extensive studies, one health related arena that has benefited greatly has been the treatment of parasitic diseases. The discovery of thiabendazole in 1961 further spurred chemists around the world to design and synthesize several thousand benzimidazoles for screening for anthelmintic activity but less than twenty of them have reached commercial use. Much of this work has been done by pharmaceutical companies and is only reported in the patent literature. In this paper, Leroy Townsend and Dean Wise review the development of some of the synthetic methods that have been critical to the preparation of the benzimidazoles of anthelmintic importance. Only a few molecules that demonstrate the processes are discussed here, but numerous reviews of the synthesis and chemistry of other benzimidazoles are available.     

2-((2-Pyridylmethyl)sulfinyl)benzimidazoles: acid sensitive suicide inhibitors of the proton transport system in the parietal cell

2-((2-Pyridylmethyl)sulfinyl)benzimidazoles, selective inhibitors of the H+/K+-ATPase in the parietal cells of the stomach, have been investigated concerning their chemical behaviour in acidic medium. Protonation of the sulfoxide and subsequent elimination of water forms a sulfenium ion or a chemical equivalent thereof. If no external nucleophiles are present, a rearrangement process takes place. In the presence of mercaptans, the sulfenium ion is trapped giving rise to a variety of products. On the basis of these results, a mechanistic scheme is proposed for the inactivation of the H+/K+-ATPase by these compounds.