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Synthesis of benzimidazole derivatives containing amide bond and biological evaluation as acetylcholinesterase, carbonic anhydrase I and II inhibitors
Abstract
Acetylcholinesterase (AChE) and carbonic anhydrase I (CA-I) and II (CA-II) are two vital metabolic enzymes. AChE inhibitors are seen as target molecules in drug development studies for Alzheimer's treatment. CA inhibitors are target molecules for treating many diseases from glaucoma to cancer. For this reason, it is crucial to identify new AChE and CA inhibitors. In this study, four benzimidazole acetamide derivatives were synthesized and their inhibition effects were investigated against human erythrocyte carbonic anhydrase I (hCA-I), II (hCA-II), and AChE. IC50 values of 9a-10b were determined in the range of 0.936 µM to 17.07 µM for AChE. IC50 values of 9a-10b for hCA-I were found as 7.21 µM, 4.72 µM, 6.08 µM, 8.23 µM, respectively. On the other hand, IC50 values of 9a-9b for hCA-II were found as 8.64 µM, 7.07 µM, 4.12 µM, 5.93 µM, respectively. According to IC50 values, 9a-10b molecules exhibited strong inhibition effects for AChE and hCAI, II. Also, Molecular docking studies were carried out to explain the binding interaction of 9a-10b with AChE, hCA-I, and hCA-II.
... The inhibition effects of four new benzimidazole derivatives bearing amide bonds 78a, 78b, 79a, and 79b against acetylcholinesterase (AChE) and human erythrocyte carbonic anhydrase I (CA-I) and II (CA-II) have been reported [81]. The activities of hCA-I and hCA-II isoenzymes were performed using esterase activity measurement protocol [82], and AChE activity in inhibition studies was performed according to the spectrophotometric approach [83]. ...
Benzimidazoles are fused heterocyclic ring systems containing two nitrogen atoms. They have vital therapeutic significance in drug discovery. Many clinically approved drugs have been developed from benzimidazole, and these include liarozole and pracinostat (anticancer), omeprazole (proton pump inhibitors), oxfendazole (Anthelmintic), enviroxine (antiviral), ilaprazole (antiulcer), ridinilazole (antibacterial), flubendazole (antiparasitic), bilastine (antihistaminic), and many more. The vast therapeutic applications of benzimidazole and its derivatives have propelled many researchers to develop more biologically active compounds bearing benzimidazole, thus broadening the scope of finding a remedy for other diseases; as a result, many new pharmaceutical drugs containing benzimidazole are expected to be available within the next decade. In this review, we describe bioactive benzimidazole hybrids in the recent year, from 2020 to 2022, to accentuate the pros of using benzimidazole in drug development.
Benzimidazole and benzoxazole derivatives are included in the category of medical drugs in a wide range of areas such as anticancer, anticoagulant, antihypertensive, anti‐inflammatory, antimicrobial, antiparasitic, antiviral, antioxidant, immunomodulators, proton pump inhibitors, hormone modulators, etc. Many researchers have focused on synthesizing more effective benzimidazole and benzoxazole derivatives for screening various biological activities. In addition, there are benzimidazole and benzoxazole rings as bioisosteres of aromatic rings found in drugs used in the treatment of Alzheimer's disease. Because of the diverse activity of the benzimidazole and benzoxazole rings and bioisosteres marketed as drugs for Alzheimer Diseases, designed compounds containing these rings are likely to be effective against Alzheimer's disease. In this study, the effectiveness of compounds containing benzimidazole and benzoxazole rings against Alzheimer's disease will be examined.
Novel quinazolinone derivatives (1‐21) were synthesized from the reaction of acylated derivatives of 4‐hydroxy benzaldehyde (AAD) with 3‐amino‐2‐alkylquinazolin‐4(3H)‐ones (QD) with good yields (85‐94%). The structures of the novel molecules were characterized using Fourier‐transform Infrared (FTIR), Nuclear Magnetic Resonance (1H NMR ‐ 13C NMR), and High‐Resolution Mass Spectroscopy (HRMS). As the application of the synthesized compounds, their inhibition properties of the synthesized compounds on α‐Glucosidase (α‐Glu), Acetylcholinesterase (AChE), Butyrylcholinesterase (BChE), and Carbonic anhydrase I‐II (hCA I‐II) metabolic enzymes were investigated. All compounds showed inhibition at nanomolar level with the Ki values in the range of 12.73±1.26 ‐ 93.42±9.44 nM for AChE, 8.48±0.92 ‐ 25.84±2.59 nM for BChE, 66.17±5.16 ‐ 818.06±44.41 for α‐Glu, 2.56±0.26 ‐ 88.23±9.72 nM for hCA‐I, and 1.68±0.14 ‐ 85.43±7.41 nM for hCA‐II. Molecular docking study was performed for understand the interactions of the most potent compounds with corresponding enzymes. Also, absorption, distribution, metabolism, excretion, and toxicity (ADME/T) properties of the compounds were investigated.
A series of N -arylmethylamide derivatives were designed and synthesized as cholinesterase inhibitors (ChEIs) for the treatment of Alzheimer’s disease (AD). Furthermore, the compounds were assayed for their inhibitory activity to cholinesterase in vitro , and the results indicated that most of the compounds had moderate inhibitory activity to cholinesterase. Among them, compound 22j showed the best inhibitory activity against BuChE (IC 50 = 0.46 µM) and moderate inhibitory activity against AChE (IC 50 = 6.52 µM); remarkably, compound 22c was found to be a dual inhibitor of AChE (IC 50 = 1.11 µM) and BuChE (IC 50 = 1.14 µM). In addition, the results of molecular docking studies exhibited that 22j could simultaneously bind to both CAS and PAS of BuChE, which was consistent with the mixed mode of inhibition shown by enzyme kinetic studies of 22j . Moreover, the molecular properties of all compounds were predicted by the molinspiration server, and the compounds 22j and 22c matched the most properties of orally administered drugs. All these suggested that 22j and 22c could be considered as a lead compound for the development of AD drugs.
In this study, a library of twelve beta-lactam-substituted benzenesulfonamides (5a-l) was synthesized using the tail-approach method. The compounds were characterized using IR, 1H NMR, 13C NMR and elemental analysis techniques. These newly synthesized compounds were tested for their ability to inhibit the activity of two carbonic anhydrases (hCA) isoforms, I and II, and acetylcholinesterase (AChE) in vitro. The results showed that the synthesized compounds were potent inhibitors of hCA I, with KIs in the low nanomolar range (66.60-278.40 nM) than the reference drug acetazolamide (AAZ), which had a KI of 439.17 nM. The hCA II was potently inhibited by compounds 5a, 5d-g and 5l, with KIs of 69.56, 39.64, 79.63, 74.76, 78.93 and 74.94 nM, respectively (AAZ, KI of 98.28 nM). Notably, compound 5a selectively inhibited hCA II with a selectivity of > 4-fold over hCA I. In terms of inhibition of AChE, the synthesized compounds had KIs ranging from 30.95 to 154.50 nM, compared to the reference drug tacrine, which had a KI of 159.61 nM. Compounds 5f, 5h and 5l were also evaluated for their ability to inhibit the MCF-7 cancer cell line proliferation and were found to have promising anticancer activity, more potent than 5-fluorouracil and cisplatin. Molecular docking studies suggested that the sulfonamide moiety of these compounds fits snugly into the active sites of hCAs and interacts with the Zn2+ ion. Furthermore, molecular dynamics simulations were performed for 200 ns to assess the stability and dynamics of each enzyme-ligand complex. The acceptability of the compounds based on Lipinski's and Jorgensen's rules was also estimated from the ADME/T results. These results indicate that the synthesized molecules have the potential to be developed into effective and safe inhibitors of hCAs and AChE and could be lead agents.Communicated by Ramaswamy H. Sarma.
Quinazolines are a group of bioactive heterocyclic compounds with a wide range of biological activities and have gained an important place in the design of active drugs with various targets due to their pharmacological properties. Carbonic anhydrase (CA) and acetylcholinesterase (AChE) inhibitors are very important pharmacologically. In this study, inhibition effects of newly synthesized quinazolin‐4(3H)‐one derivatives on human erythrocyte CA‐I (hCA‐I) and CA‐II (hCA‐II) isoenzyme and AChE activity were investigated. The structures of the novel compounds were characterized by fourier‐transform infrared (FTIR), nuclear magnetic resonance (NMR), and high‐resolution mass spectroscopy (HRMS). All molecules showed strong inhibitory effect in all three enzymes. 4‐[(4‐Oxo‐2‐(phenoxymethyl)quinazolin‐3(4H)‐ylimino)methyl]phenyl furan‐2‐carboxylate for hCA‐I (IC50: 205 nM), 4‐[(4‐oxo‐2‐(phenoxymethyl)quinazolin‐3(4H)‐ylimino)methyl]phenyl isobutyrate for hCA‐II (IC50: 209 nM), and 4‐[(4‐oxo‐2‐(phenoxymethyl)quinazolin‐3(4H)‐ylimino)methyl]phenyl propionate for AChE (IC50: 14.2 nM) were the molecules that showed the strongest inhibitory effect. Molecular docking studies were carried out to elucidate the possible interaction mechanism of the molecules in the active site of the enzymes. The affinity scores of the most active compounds for hCA‐I, hCA‐II, and AChE were determined as −134.765, −147.423, and −175.354 MolDock Score, respectively.
Acetylcholinesterase (AChE) and paraoxonase 1 (PON1) are two important serum ester hydrolases that have antiatherosclerotic effect by inhibiting the oxidation of lipid peroxides. In addition, AChE inhibitors are target molecules for the treatment of Alzheimer's. Naphthalene derivatives are important molecules in the field of pharmacology due to their wide range of biological activities. In this study, the inhibition effects of naphthalenylmethylen hydrazine derivatives on these two metabolic enzymes were investigated. IC50 values of these molecules were determined in the range of 0.158 μM to 6.862 μM against PON1, 0.0214 μM to 0.675 μM against AChE. As a result, naphthalenylmethylen hydrazine derivatives had strong inhibition effect on both enzymes. In this context, we hope that the results obtained in this study contribute to the determination of the side effects of current and new naphthalene‐based pharmacological compounds to be developed. And also be effective in the synthesis studies of new AChE inhibitors.
In this study, two novel metallophthalocyanines (ZnPc and CoPc) were synthesized using the corresponding metal salts 4‐(4‐(4‐[4‐chlorophenyl]‐5‐methylisoxazol‐3‐yl)phenoxy)‐phthalonitrile (11), prepared from the reaction of 4‐nitrophthalonitrile and 4‐(4‐[4‐chlorophenyl]‐5‐methylisoxazol‐3‐yl)phenol (9). These metallophthalocyanines (MPcs) showed quite solubility in organic solvents such as dichloromethane (DCM), tetrahydrofuran (THF), dimethyl formamide (DMF), and dimethylsulfoxide (DMSO). The novel compounds 11a and 11b have been characterized using their UV–Vis, FT–IR, 1H NMR, 13C NMR, X‐Ray, and MALDI–TOF mass spectra. Supporting information cocerning with the study has been supplied. Photochemical, photophysical, and cyclic voltagram properties of these novel 4‐(4‐(4‐[4‐chlorophenyl]‐5‐methylisoxazol‐3‐yl)phenoxy substituted metallophthalocyanines (11a and 11b) were determined in DMF. DNA binding, metal chelating effect assay, and DPPH [2,2‐diphenyl‐1‐picrylhydrazyl hydrate] radical scavenging assay and electrochemical studies of MPcs were investigated. Further, the inhibitory effects of the COX‐inhibitor based novel metallophthalocyanines (11a and 11b) and their ligands (10 and 11) were examined on human erythrocyte carbonic anhydrase I (hCA‐I) and II (hCA‐II) isoenzymes, and the synthesized molecules exhibited very strong inhibitory effects on both isoforms. In addition, the hCA‐I and hCA‐II inhibition potential of Zn (II) and Co (II) Phthalocyanine complexes was supported by molecular docking studies. The binding interaction of metallophthalocyanines complexes 11a, 11b enzymes were analyzed in detail.
In this study, three new Schiff bases have been synthesized by the reactions of commercially available phenylglycinol, phenylalaninol, and leuicinol with 4-{[2-(4-formylphenoxy)ethyl](methyl)amin}benzaldehyde and characterized by ¹H and ¹³C NMR, FTIR, and UV-Vis spectroscopy and LCMS/MS. In vitro effects of synthesized new Schiff bases on human erythrocyte carbonic anhydrase I (hCA I) and II (hCA II) isoenzymes and acetylcholinesterase (AChE) activity were investigated. Schiff base synthesized from phenylglycinol showed no meaningful effect on hCAI and hCAII. Schiff bases synthesized from phenylalaninol and leuicinol exhibited a strong activation effect on hCAI and hCAII. On the other hand, all of the synthesized three Schiff bases exhibited a strong inhibitory effect on AChE activity.
A series of novel amide functionalized 1H‐benzo[d]imidazole‐2‐thiol derivatives 4 a‐o were prepared from substituted benzimidazole‐2‐thiol 1 a‐c. All the final compounds were screened for antimicrobial, minimum bactericidal concentration (MBC) and anti‐biofilm activities against Gram‐positive and Gram‐negative bacterial strains. Amongst all the synthesized derivatives, compounds 4 c, 4 e, 4 f, 4 g, 4 k and 4 o exhibiting promising antibacterial activity against various bacterial strains were identified. Moreover, the compound 4 c showed highly significant antimicrobial activity (MIC value of 1.9 μg/mL) and broad‐spectrum anti‐biofilm activity which was identified as a potential lead molecule.
In this paper, we described the synthesis of 3‐[(1H‐benzimidazol‐2‐ylsulfanyl)(aryl) methyl]‐4‐hydroxy‐2H‐chromen‐2‐one derivatives by one‐pot three‐component reaction between 4‐hydroxycoumarin, substituted aldehydes and 2‐mercaptobenzimidazole in the presence of L‐proline as a catalyst. The structures of the synthesized compounds were characterized by FT‐IR, NMR and Mass spectral data. Further, the synthesized compounds were screened for antimicrobial and antioxidant activities. Molecular docking studies were also carried out to know the inhibitory effect of the synthesized compounds against pathogens.
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) belong to an important therapeutic class for treatment of type 2 diabetes. Six GLP-1 RAs, each utilizing a unique drug delivery strategy, are now approved by the Food and Drug Administration (FDA) and additional, novel GLP-1 RAs are still under development, making for a crowded marketplace and fierce competition among the manufacturers of these products. As rapid elimination is a major challenge for clinical application of GLP-1 RAs, various half-life extension strategies have been successfully employed including sequential modification, attachment of fatty-acid to peptide, fusion with human serum albumin, fusion with the fragment crystallizable (Fc) region of a monoclonal antibody, sustained drug delivery systems, and PEGylation. In this review, we discuss the scientific rationale of the various half-life extension strategies used for GLP-1 RA development. By analyzing and comparing different approved GLP-1 RAs and those in development, we focus on assessing how half-life extending strategies impact the pharmacokinetics, pharmacodynamics, safety, patient usability and ultimately, the commercial success of GLP-1 RA products. We also anticipate future GLP-1 RA development trends. Since similar drug delivery strategies are also applied for developing other therapeutic peptides, we expect this case study of GLP-1 RAs will provide generalizable concepts for the rational design of therapeutic peptides products with extended duration of action.
New coumarin-benzimidazole hybrids (3a?f) have been synthesized from 4-formylcoumarins and a series of N-sulphonation (4?a-f) and N-methylation (5?a-f) compounds were obtained from compounds (3a?f). All the synthesized compounds have exhibited good antimicrobial activity. Docking studies provide valuable insights to potential binding modes of inhibitors. Anti cancer activity of compound 4?a and 4?c have shown excellent activity against HeLa cell line. Whereas compound 4?a and 4?d exhibited higher activity against HT 29 cell lines. We calculated the LC50, TGI and GI50 which show < 10?mg/mL. The synthesized compounds were characterized by IR, NMR, Mass spectral analysis and few of them by single X-ray crystallography analysis.
Recent advances in the study of the catalytic properties of acetylcholinesterases have been reviewed. The main biological function of this enzyme is the fast termination of impulse transmission at cholinegric synapses by rapid hydrolysis of the neurotransmitter acetylcholine. Acetylcholinesterase has been often characterized as a perfect enzyme because its catalytic properties have been tuned to the highest possible limit. However, it seems paradoxical that the active site of this enzyme is buried deeply inside the enzyme molecule in the bottom of a narrow gorge restricting the traffic of substrates and products. The analysis of recent advances in enzymology and data on cholinesterase revealed rationality of this organization. The primary task of an enzyme catalyst is to lower the activation barrier for the chemical transformation of the substrate, and the catalytic power of the enzyme originates in polar solvation of the transition state by properly oriented dipoles inside the enzyme molecule. The active site gorge of acetylcholinesterase, containing multiple potential substrate binding areas, is responsible for trapping and delivery of substrate molecules to the active site. The phenomena of allosteric modulation and substrate inhibition arise as secondary effects of the presence of the narrow gorge lined with hydrophobic residues.
The methods of theoretical chemistry have been used to elucidate molecular properties of clinically useful acetazolamide, dorzolamide and brinzolamide and two new aromatic sulfonamides in both neutral and deprotonated forms. The geometries and energies of these drugs have been computed using HF/6–31G(d), Becke3LYP/6–31G(d) and Becke3LYP/6–311+G(d,p) model chemistries. The equilibrium structure of the acetazolamide is stabilized via intramolecular interaction between non-bonded S···O atoms of the acetylamino group and the thiadiazole ring. In the case of the aromatic sulfonamides (4-sulfamoyl-N-(3-morpholinopropyl) benzamide (P10), and N-(morpholinopropyl)benzene-1,4-bis(sulfonamide) (P20)) the fully optimized most stable conformers possess characteristic L-shape structure stabilized via intramolecular hydrogen bonding system of the N–H···N type. Computed partition coefficients (XLOGP2 method) for drugs studied varied between –0.3 and –1.8. Neutral compounds are described as slightly lipophilic drugs. The calculated water solubility of dorzolamide and brinzolamide is comparably low. P10 and P20 are slightly lipophilic sulfonamides with moderate solubility. The calculated pKa values of –SO2NH2 moiety in the sulfonamides studied are in the range of 7.3–9.7 and are characterized as weak organic acids.
Synthesis and biological evaluation of some novel 2-phenyl benzimidazole-1-acetamide derivatives as potential anthelmintic agents
The present study describes synthesis of a series of 2-phenyl benzimidazole-1-acetamide derivatives and their evaluation for anthelmintic activity using Indian adult earthworms, Pheretima posthuma. The structure of the title compounds was elucidated by elemental analysis and spectral data. The compounds 4-({[2-(4-nitrophenyl)-1 H -benzimidazol-1-yl]acetyl}amino) benzoic acid ( 3a ), N -ethyl-2-[2-(4-nitrophenyl)-1 H -benzimidazol-1-yl] acetamide ( 3c ), N -benzyl-2-[2-(4-nitrophenyl)-1 H -benzimidazol-1-yl] acetamide ( 3d ), N -(4-hydroxyphenyl)-2-[2-(4-nitrophenyl)-1 H -benzimidazol-1-yl] acetamide ( 3f ), 2-[2-(4-nitrophenyl)-1 H -benzimidazol-1-yl]- N -phenyl acetamide ( 3h ), 2-[2-(4-chlorophenyl)-1 H -benzimidazol-1-yl]- N' -phenylacetohydrazide ( 3k ), 2-[2-(4-chlorophenyl)-1 H -benzimidazol-1-yl]- N -(4-nitrophenyl) acetamide ( 3n ) and 2-[2-(4-chlorophenyl)-1 H -benzimidazol-1-yl]- N -phenyl acetamide ( 3q ) were found better to paralyze worms whereas N -ethyl-2-[2-(4-nitrophenyl)-1 H -benzimidazol-1-yl] acetamide ( 3c ), N-(4-nitrophenyl)-2-[2-(4-nitrophenyl)-1 H -benzimidazol-1-yl] acetamide ( 3e ), 4-({[2-(4-chlorophenyl)-1 H -benzimidazol-1-yl] acetyl}amino) benzoic acid ( 3j ), 2-[2-(4-chlorophenyl)-1 H -benzimidazol-1-yl]- N -ethyl acetamide ( 31 ) and 2-[2-(4-chlorophenyl)-1 H -benzimidazol-1-yl]- N -phenyl acetamide ( 3q ) were better to cause death of worms compared to the anthelmintic drug albendazole.
Bacterial biofilm formation causes significant industrial economic loss and high morbidity and mortality in medical settings.
Biofilms are defined as multicellular communities of bacteria encased in a matrix of protective extracellular polymers. Because
biofilms have a high tolerance for treatment with antimicrobials, protect bacteria from immune defense, and resist clearance
with standard sanitation protocols, it is critical to develop new approaches to prevent biofilm formation. Here, a novel benzimidazole
molecule, named antibiofilm compound 1 (ABC-1), identified in a small-molecule screen, was found to prevent bacterial biofilm
formation in multiple Gram-negative and Gram-positive bacterial pathogens, including Pseudomonas aeruginosa and Staphylococcus aureus, on a variety of different surface types. Importantly, ABC-1 itself does not inhibit the growth of bacteria, and it is effective
at nanomolar concentrations. Also, coating a polystyrene surface with ABC-1 reduces biofilm formation. These data suggest
ABC-1 is a new chemical scaffold for the development of antibiofilm compounds.
The development of high-temperature PEM fuel cells (working at 150-200 degrees C) is pursued worldwide in order to solve some of the problems of current cells based on Nafion (CO tolerance, improved kinetics, water management, etc.). Polybenzimidazole membranes nanoimpregnated with phosphoric acid have been studied as electrolytes in PEMFCs for more than a decade. Commercially available polybenzimidazole (PBI) has been the most extensively studied and used for this application in membranes doped with all sorts of strong inorganic acids. In addition to this well-known polymer we also review here studies on ABPBI and other polybenzimidazole type membranes. More recently, several copolymers and related derivatives have attracted many researchers' attention, adding variety to the field. Furthermore, besides phosphoric acid, many other strong inorganic acids, as well as alkaline electrolytes have been used to impregnate benzimidazole membranes and are analyzed here. Finally, we also review different hybrid materials based on polybenzimidazoles and several inorganic proton conductors such as heteropoly acids, as well as sulfonated derivatives of the polymers, all of which contribute to a quickly-developing field with many blooming results and useful potential which are the subject of this critical review (317 references).
Both human carbonic anhydrases B and C act as esterases on o- and p-nitrophenyl acetates. Enzyme C is the more active of the two for the hydrolysis of p-nitrophenyl acetate, and enzyme B for o-nitrophenyl acetate. The pH-activity curves are sigmoid, the esterase activity being very small below pH 6 and rising to a high level around pH 9; the inflection point lies at pH 7.3 for Enzyme B and at 6.8 for Enzyme C. The Km values are nearly independent of pH in all cases; thus the pH dependence curves appear to reflect the catalytic center activity. The reactions follow Michaelis-Menten kinetics over the range of substrate concentrations studied, but this range is limited to values less than the Km values, because of the limited solubility of the esters.
Measurements in a stop-flow apparatus, at times from 10 msec to 2 sec, gave the same kinetic constants as those measured under steady state conditions. There was no evidence of an initial “burst” of release of nitrophenol. When the reactions were studied under the condition (E0) ≅ (S0) << Km, the process followed first order kinetics until hydrolysis was nearly complete. The data thus gave no evidence for the presence of an acyl intermediate; if such an intermediate exists it must be very rapidly hydrolyzed.
Both enzymes are inhibited by monovalent anions, by acetazolamide, and by alcohols. Anion inhibition decreases with increasing pH, and so does the acetazolamide inhibition. The alcohol inhibition is not affected by pH. Enzyme B is somewhat more strongly inhibited by anions, but Enzyme C is much more strongly inhibited by alcohols and by acetazolamide. Only one site seems to be involved in the inhibition by either type of inhibitor. Competition for one site has been demonstrated between the anions and the alcohols. The inhibitions are reversible, and noncompetitive with respect to substrate.
Since anion inhibition follows the lyotropic series, the binding site is believed not to be the zinc ion. Binding of anions by Enzyme B, and by zinc-free apoenzyme, has been demonstrated by an increase in pH of an isoionic solution caused by the addition of neutral salts. At low salt concentrations solutions of the apoenzyme show a lower change in pH than these of the holoenzyme, but at higher salt concentrations the values are very similar. Thus in 0.1 m KCl both the enzyme and apoenzyme bind approximately 6 chloride ions.
Binding sites of Torpedo acetylcholinesterase (EC 3.1.1.7) for quaternary ligands were investigated by x-ray crystallography and photoaffinity labeling. Crystal structures of complexes with ligands were determined at 2.8-A resolution. In a complex with edrophonium, and quaternary nitrogen of the ligand interacts with the indole of Trp-84, and its m-hydroxyl displays bifurcated hydrogen bonding to two members of the catalytic triad, Ser-200 and His-440. In a complex with tacrine, the acridine is stacked against the indole of Trp-84. The bisquaternary ligand decamethonium is oriented along the narrow gorge leading to the active site; one quaternary group is apposed to the indole of Trp-84 and the other to that of Trp-279, near the top of the gorge. The only major conformational difference between the three complexes is in the orientation of the phenyl ring of Phe-330. In the decamethonium complex it lies parallel to the surface of the gorge; in the other two complexes it is positioned to make contact with the bound ligand. This close interaction was confirmed by photoaffinity labelling by the photosensitive probe 3H-labeled p-(N,N-dimethylamino)benzenediazonium fluoroborate, which labeled, predominantly, Phe-330 within the active site. Labeling of Trp-279 was also observed. One mole of label is incorporated per mole of AcChoEase inactivated, indicating that labeling of Trp-279 and that of Phe-330 are mutually exclusive. The structural and chemical data, together, show the important role of aromatic groups as binding sites for quaternary ligands, and they provide complementary evidence assigning Trp-84 and Phe-330 to the "anionic" subsite of the active site and Trp-279 to the "peripheral" anionic site.
The efficacy and safety of the two antihistamines, astemizole and loratadine, were compared in a double-blind study of 84 patients with perennial allergic rhinitis. Patients were randomized to receive orally either astemizole 10 mg once daily (n = 40) or loratadine 10 mg once daily (n = 44) for 1 week. No other antirhinitis medication was allowed during the study. By day 7 the mean daily symptom scores, recorded on diary cards, were lower in patients receiving astemizole than in those receiving loratadine for runny nose, itchy nose and sneezing, although not for blocked nose, and treatment differences only reached statistical significance for runny nose. After 7 days, 53.75% of patients on astemizole and 38.6% on loratadine were free of symptoms, and 87% of patients on astemizole described the treatment as good or excellent compared with 62% on loratadine. The present results suggest that astemizole may be more effective than loratadine in controlling symptoms of perennial allergic rhinitis.
CO(2) produced within skeletal muscle has to leave the body finally via ventilation by the lung. To get there, CO(2) diffuses from the intracellular space into the convective transport medium blood with the two compartments, plasma and erythrocytes. Within the body, CO(2) is transported in three different forms: physically dissolved, as HCO(3)(-), or as carbamate. The relative contribution of these three forms to overall transport is changing along this elimination pathway. Thus the kinetics of the interchange have to be considered. Carbonic anhydrase accelerates the hydration/dehydration reaction between CO(2), HCO(3)(-), and H(+). In skeletal muscle, various isozymes of carbonic anhydrase are localized within erythrocytes but are also bound to the capillary wall, thus accessible to plasma; bound to the sarcolemma, thus producing catalytic activity within the interstitial space; and associated with the sarcoplasmic reticulum. In some fiber types, carbonic anhydrase is also present in the sarcoplasm. In exercising skeletal muscle, lactic acid contributes huge amounts of H(+) and by these affects the relative contribution of the three forms of CO(2). With a theoretical model, the complex interdependence of reactions and transport processes involved in CO(2) exchange was analyzed.
Alzheimer's disease (AD) is the most devastating and progressive neurodegenerative disease in middle to elder aged people, which can be exacerbated by lifestyle factors. Recent longitudinal studies demonstrated that alcohol consumption exacerbates memory impairments in adults. However, the underlying mechanism of alcohol-induced memory impairment is still elusive. The increased cellular manifestation of reactive oxygen species (ROS) and the production of numerous proinflammatory markers play a critical role in the neurodegeneration and pathogenesis of AD. Therefore, reducing neurodegeneration by decreasing oxidative stress and neuroinflammation may provide a potential therapeutic roadmap for the treatment of AD. In this study, eight new benzimidazole acetamide derivatives (FP1, FP2, FP5-FP10) were synthesized and characterized to investigate its neuroprotective effects in ethanol-induced neurodegeneration in a rat model. Further, three derivatives (FP1, FP7, and FP8) were selected for in vivo molecular analysis based on preliminary in vitro antioxidant screening assay. Molecular docking analysis was performed to assess the affinity of synthesized benzimidazole acetamide derivatives against selected proinflammatory targets (TNF-α, IL-6). Biochemical analysis revealed elevated expression of neuroinflammatory markers (TNF-α, NF-κB, IL-6, NLRP3), increased cellular oxidative stress, and reduced antioxidant enzymes in ethanol-exposed rats brain. Notably, pretreatment with new benzimidazole acetamide derivatives (FP1, FP7, and FP8) significantly modulated the ethanol-induced memory deficits, oxidative stress, and proinflammatory markers (TNF-α, NF-κB, IL-6, NLRP3) in the cortex. The multipurpose nature of acetamide containing benzimidazole nucleus and its versatile affinity toward numerous receptors highlight its multistep targeting potential. These results indicated the neuroprotective potential of benzimidazole acetamide derivatives (FP1, FP7, and FP8) as novel therapeutic candidates in ethanol-induced neurodegeneration which may partially be due to inhibition of the neuroinflammatory-oxidative stress vicious cycle.
Background
Thiophene(s) are an important group in therapeutic applications, and sulfonamides are the most important class of carbonic anhydrase (CA) inhibitors. In this study, inhibition effects of some thiophene-based sulfonamides on human erythrocytes carbonic anhydrase I and II isoenzymes (hCA-I and hCA-II) were investigated. Thiophene-based sulfonamides used in this study showed potent inhibition effect on both isoenzymes at very small concentrations.Materials and methodsWe report on the purification of the carbonic anhydrase I and II isoenzymes (hCA-I and hCA-II) using affinity chromatography method. The inhibition effect of the thiophene-based sulfonamides was determined by IC50 and Ki parameters. A molecular docking study was performed for each molecule.ResultsThiophene-based sulfonamides showed IC50 values of in the range of 69 nM to 70 µM against hCA-I, 23.4 nM to 1.405 µM against hCA-II. Ki values were in the range of 66.49 ± 17.15 nM to 234.99 ± 15.44 µM against hCA-I, 74.88 ± 20.65 nM to 38.04 ± 12.97 µM against hCA-II. Thiophene-based sulfonamides studied in this research showed noncompetitive inhibitory properties on both isoenzymes. To elucidate the mechanism of inhibition, a molecular docking study was performed for molecules 1 and 4 exhibiting a strong inhibitory effect on hCA-I and hCA-II. The compounds inhibit the enzymes by interacting out of catalytic active site. The sulfonamide and thiophene moiety played a significant role in the inhibition of the enzymes.Conclusion
We hope that this study will contribute to the design of novel thiophene-based sulfonamide derived therapeutic agents that may be carbonic anhydrase inhibitors in inhibitor design studies.
Three new heterocyclic benzimidazole derivatives and has been synthesized and characterized via different spectroscopic methods (¹H, ¹³C NMR) and study their inhibitory properties of three benzimidazole derivatives, namely: 2- (2- (4-chlorophenyl) -1H-benzo [d] imidazol-1-yl) -N- (p-tolyl) acetamide (CBIN-1), 2- (2- (4-chlorophenyl) -1H) benzo [d] imidazol-1-yl) -N- (3,5-dimethylphenyl) acetamide (CBIN-2) and 2- (2- (4-chlorophenyl) -1H-benzo [d] imidazol-1-yl)) -N-phenylacetamide (CBIN-3) for carbon steel (CS) in 1 M HCl solution using electrochemical impedance spectroscopy, potentiodynamic polarization and weight loss measurements at 298 K. The experimental results show that the inhibition increases with the concentration and can reach a limit value of 95.0% for the inhibitor
CBIN-2 at 10⁻³ M. The polarization curves show that the benzimidazole derivatives (CBIN-1, CBIN-2 and CBIN-3) are of mixed type. The increase in temperature may have a decrease in the inhibition efficacy of the compounds studied. In addition, the inhibitors obey the single layer adsorption isotherm of Langmuir. It is found that the experimental parameters confirmed those obtained by theoretical studies. Surface morphology using SEM coupled and UV–visible spectroscopy of the carbon steel treated was investigated and discussed.
The synthesis, characterization and biological evaluation of a series of novel N-substituted phthalazine sulfonamide (5a-l) are disclosed. Phthalazines which are nitrogen-containing heterocyclic compounds are biologically preferential scaffolds, endowed with versatile pharmacological activity, such as anti-inflammatory, cardiotonic vasorelaxant, anticonvulsant, antihypertensive, antibacterial, anti-cancer action. The compounds were investigated for the inhibition against the cytosolic hCA I, II and AChE. Most screened sulfonamides showed high potency in inhibiting hCA II, widely involved in glaucoma, epilepsy, edema, and other pathologies (Kis in the ranging from 6.32±0.06 to 128.93±23.11 nM). hCA I was inhibited with Kis in the range of 6.80±0.10-85.91±7.57 nM, whereas AChE in the range of 60.79±3.51-249.55±7.89 nM. ADME prediction study of the designed N-substituted phthalazine sulfonamides showed that they are not only with carbonic anhydrase and acetylcholinesterase inhibitory activities but also with appropriate pharmacokinetic, physicochemical parameters and drug-likeness properties. Also, in silico docking studies were investigated the binding modes of selected compounds, to hCA I, II, and AChE.
Human carbonic anhydrase I and II isoenzymes (hCA I and II) and acetylcholinesterase (AChE) are important metabolic enzymes that are closely associated with various physiological and pathological processes. In this study, we investigated the inhibition effects of some sulfonamides on hCA I, hCA II, and AChE enzymes. Both hCA isoenzymes were purified by Sepharose‐4B‐L‐Tyrosine‐5‐amino‐2‐methylbenzenesulfonamide affinity column chromatography with 1393.44 and 1223.09‐folds, respectively. Also, some inhibition parameters including IC50 and Ki values were determined. Sulfonamide compounds showed IC 50 values of in the range of 55.14 to 562.62 nM against hCA I, 55.99 to 261.96 nM against hCA II, and 98.65 to 283.31 nM against AChE. Ki values were in the range of 23.40 ± 9.10 to 365.35 ± 24.42 nM against hCA I, 45.87 ± 5.04 to 230.08 ± 92.23 nM against hCA II, and 16.00 ± 45.53 to 157.00 ± 4.02 nM against AChE. As a result, sulfonamides had potent inhibition effects on these enzymes. Therefore, we believe that these results may contribute to the development of new drugs particularly in the treatment of some disorders.
Seventeen novel 2,5‐disubstituted benzimidazole derivatives were designed, synthesized and evaluated for their antibacterial activities. The tested compounds B1–B4 and C2–C6 exhibited not only good antifungal activity but also favorable broad‐spectrum antibacterial activity. Also, the lowest MIC of antibacterial and antifungal activity was 2 μg/mL and 4 μg/mL, respectively. It suggested that the structure of compound including the different substituent and its sites directly affected on efficacy of the synthesized compound.
Carbonic anhydrase (CA) is an important metabolic enzyme family closely related to many physiological and pathological processes. Currently, carbonic anhydrase inhibitors are the target molecules in the treatment and diagnosis of many diseases. In present study, we investigated the inhibitory effects of some indazole molecules on the CA‐I and CA‐II isoenzymes isolated from human erythrocytes. We showed that human CA‐I and CA‐II activities were reduced by of some indazoles at low concentrations. IC50 values, Ki constants, and inhibition types for each indazole molecule were determined. The indazoles showed Ki constants in a range of 0.383 ± 0.021 to 2.317 ± 0.644 mM, 0.409 ± 0.083 to 3.030 ± 0.711 mM against CA‐I and CA‐II, respectively. Each indazole molecule exhibited a noncompetitive inhibition effect. Bromine‐ and chlorine‐bonded indazoles were found to be more potent inhibitory effects on carbonic anhydrase isoenzymes. In conclusion, we conclude that these results may be useful in the synthesis of carbonic anhydrase inhibitors.
A novel N-acyl substituted indole-linked benzimidazoles and naphthoimidazoles were synthesized. Their chemical structures were confirmed using spectroscopic tools including 1H NMR, 13C NMR and CHN-elemental analyses. Anti inflammatory activity for all target compounds was evaluated in-vitro. The synthesized compounds hinder the biofilm formation and control the growth of the pathogen, Staphylococcus epidermis. Anti microbial activity of the compounds was evaluated against both Gram negative and Gram positive bacteria such as Staphylococcus aureus (MTCC 2940), Pseudomonas aeruginosa (MTCC424), Escherchia coli (MTCC 443) and Enterococcus fecalis.
Chiral aspects of benzimidazoles have been over-shadowed for a long time due to the large number of reports on benzimidazoles in the medical field in numerous categories of therapeutic agents. The vigorous research activity in chiral applications of benzimidazole derivatives started after bifunctional benzimidazoles made their appearance especially in the last 2-3 decades. Thus, chiral benzimidazoles form a comparatively young branch of chiral chemistry. The presence of pyridine and pyrrole type of nitrogens along with the fused benzene ring confer on this class of molecules, special properties including useful nucleophilicity, hydrogen bonding ability and a rigid backbone, all of which play decisive roles in proven chiral applications. The present review aims to cover the synthetic routes to access chiral benzimidazoles and their applications in a plethora of chiral fields including enantioselective organocatalysis, metal-based catalysis, asymmetric transformations involving benzimidazole-N-heterocyclic carbenes, kinetic resolution, benzimidazole-based macrocyclic hosts in chiral supramolecular chemistry and other miscellaneous chiral applications.
To date, the pharmacotherapy of Alzheimer's disease (AD) has relied on acetylcholinesterase (AChE) inhibitors (AChEIs) and, more recently, an N-methyl-D-aspartate receptor (NMDAR) antagonist. AD is a multifactorial syndrome with several target proteins contributing to its etiology. "Multi-target-directed ligands" (MTDLs) have great potential for treating complex diseases such as AD because they can interact with multiple targets. The design of compounds that can hit more than one specific AD target thus represents an innovative strategy for AD treatment. Tacrine was the first AChEI introduced in therapy. Recent studies have demonstrated its ability to interact with different AD targets. Furthermore, numerous tacrine homo- and heterodimers have been developed with the aim of improving and enlarging its biological profile beyond its ability to act as an AChEI. Several tacrine hybrid derivatives have been designed and synthesized with the same goal. This review will focus on and summarize the last two years of research into the development of tacrine derivatives able to hit AD targets beyond simple AChE inhibition.
Several bifunctional organocatalysts bearing the 2-aminobenzimidazole unit have been designed in order to act as bifunctional systems by hydrogen bonding. Chiral 2-aminobenzimidazoles are conformational rigid guanidines able to catalyze enantioselectively Michael reaction, direct SN1 of alcohols and aldol reactions. Some of these organocatalysts can be easily recovered by simple isolation methods and reused without loss of catalytic activity. Related (2-aminoalkyl)benzimidazoles have been used as chiral organocatalysts in aldol and amination reactions of carbonyl compounds.
Carbonic anhydrases (CAs) are known as a drug target enzymes. The inhibitors of the enzyme are important compounds for discovery new therapeutic agents and understanding in detail protein-drug interactions at molecular level. For this purpose, the in vitro effects of some anti-inflammatory agents such as tenoxicam, fluorometholone acetate and dexamethasone were investigated on esterase activity of human erythrocyte CA-I and II in this study. hCAI and II were purified by affinity chromatography with a yield of 47.25% and 87%, a specific activity of 642.8 EU/mg proteins and 5576.9 EU/mg proteins, respectively. SDS-PAGE was performed to determine the purity of the enzymes. Inhibitory effects of the drugs on hCA-I and II were determined by using spectrophotometric method. IC50 values for hCA-I and II were 0.198 μM, 2.18 μM, 11.7 μM for hCA-I and 0.11 μM, 17.5 μM, 14 μM for tenoxicam, fluorometholone acetate and dexamethasone, respectively. For fluorometholone acetate, dexamethasone Ki values from Lineweaver-Burk plots were obtained as 1.044 μM (noncompetitive), 21.2 μM (noncompetitive) for hCA-I and 9.98 μM (noncompetitive), 8.66 μM (noncompetitive) for hCA-II. In conclusion, tenoxicam, fluorometholone acetate, dexamethasone showed potent inhibition effects on esterase activity of hCA-I and II isozymes under in vitro conditions. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Within the vast range of heterocycles, benzimidazole and its derivatives are found to be trendy structures employed for discovery of drugs in the field of pharmaceutical and medicinal chemistry. The unique structural features of benzimidazole and a wide range of biological activities of its derivatives made it privileged structure in drug discovery. Recently, benzimidazole scaffold has emerged as a pharmacophore of choice for designing analgesic and anti-inflammatory agents active on different clinically approved targets. To pave the way for future research, there is a need to collect the latest information in this promising area. In the present review we have collated published reports on this versatile core to provide an insight so that its full therapeutic potential can be utilized for the treatment of pain and inflammation.
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To affiliate multiple bioactivities in a compact heteronuclei, two series of benzimidazole based 1,3,4-oxadiazoles were synthesized and assessed in vitro for their efficacy as antimicrobial agents against eight bacteria (Staphylococcus aureus, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Salmonella typhi, Proteus vulgaris, Shigella flexneri), four fungi (Aspergillus niger, Aspergillus fumigatus, Aspergillus clavatus, Candida albicans) and Mycobacterium tuberculosis H37Rv and best results were observed amongst the N-benzothiazolyl aetamide series. The lipophilicity (LogP) influence on the biological profile (MICs) of the prepared products was also discussed. Upon biological screening, it was observed that the majority of the compounds were found to possess a significant broad spectrum antimicrobial (3.12-25 μg/mL of MIC) and antitubercular (6.25-25 μg/mL of MIC) potential. The structural assignments of the new products were done on the basis of IR, (1)H NMR, (13)C NMR spectroscopy and elemental analysis.
A photometric method for determining acetylcholinesterase activity of tissue extracts, homogenates, cell suspensions, etc., has been described. The enzyme activity is measured by following the increase of yellow color produced from thiocholine when it reacts with dithiobisnitrobenzoate ion. It is based on coupling of these reactions: The latter reaction is rapid and the assay is sensitive (i.e. a 10 μ1 sample of blood is adequate). The use of a recorder has been most helpful, but is not essential. The method has been used to study the enzyme in human erythrocytes and homogenates of rat brain, kidney, lungs, liver and muscle tissue. Kinetic constants determined by this system for erythrocyte eholinesterase are presented. The data obtained with acetylthiocholine as substrate are similar to those with acetylcholine.
Three isoforms of nitric oxide synthase (NOS), dimeric enzymes that catalyze the formation of nitric oxide (NO) from arginine, have been identified. Inappropriate or excessive NO produced by iNOS and/or nNOS is associated with inflammatory and neuropathic pain. Previously, we described the identification of a series of amide-quinolinone iNOS dimerization inhibitors that although potent, suffered from high clearance and limited exposure in vivo. By conformationally restricting the amide of this progenitor series, we describe the identification of a novel series of benzimidazole-quinolinone dual iNOS/nNOS inhibitors with low clearance and sustained exposure in vivo. Compounds were triaged utilizing an LPS challenge assay coupled with mouse and rhesus pharmacokinetics and led to the identification of 4,7-imidazopyrazine 42 as the lead compound. 42 (KD7332) (J. Med. Chem. 2009, 52, 3047 - 3062) was confirmed as an iNOS dimerization inhibitor and was efficacious in the mouse formalin model of nociception and Chung model of neuropathic pain, without showing tolerance after repeat dosing. Further 42 did not affect motor coordination up to doses of 1000 mg/kg, demonstrating a wide therapeutic margin.
To date, the pharmacotherapy of Alzheimer's disease (AD) has relied on acetylcholinesterase (AChE) inhibitors (AChEIs) and, more recently, an N-methyl-D-aspartate receptor (NMDAR) antagonist. AD is a multifactorial syndrome with several target proteins contributing to its etiology. "Multi-target-directed ligands" (MTDLs) have great potential for treating complex diseases such as AD because they can interact with multiple targets. The design of compounds that can hit more than one specific AD target thus represents an innovative strategy for AD treatment. Tacrine was the first AChEI introduced in therapy. Recent studies have demonstrated its ability to interact with different AD targets. Furthermore, numerous tacrine homo- and heterodimers have been developed with the aim of improving and enlarging its biological profile beyond its ability to act as an AChEI. Several tacrine hybrid derivatives have been designed and synthesized with the same goal. This review will focus on and summarize the last two years of research into the development of tacrine derivatives able to hit AD targets beyond simple AChE inhibition.
A protein determination method which involves the binding of Coomassie Brilliant Blue G-250 to protein is described. The binding of the dye to protein causes a shift in the absorption maximum of the dye from 465 to 595 nm, and it is the increase in absorption at 595 nm which is monitored. This assay is very reproducible and rapid with the dye binding process virtually complete in approximately 2 min with good color stability for 1 hr. There is little or no interference from cations such as sodium or potassium nor from carbohydrates such as sucrose. A small amount of color is developed in the presence of strongly alkaline buffering agents, but the assay may be run accurately by the use of proper buffer controls. The only components found to give excessive interfering color in the assay are relatively large amounts of detergents such as sodium dodecyl sulfate, Triton X-100, and commercial glassware detergents. Interference by small amounts of detergent may be eliminated by the use of proper controls.
Clinical manifestations in patients with carbonic anhydrase (CA) II deficiency include osteopetrosis, renal tubular acidosis, and cerebral calcification. Of the 39 reported cases of the carbonic anhydrase II deficiency syndrome, 72% were patients from North African and Middle Eastern countries, most, if not all, of whom were of Arabic descent. We have analyzed DNAs from members of six unrelated Arabic kindreds and found five to be homozygous and one heterozygous for a novel splice junction (donor site) mutation at the 5' end of intron 2. These findings suggest that a common "Arabic" mutation may be the predominant cause of CA II deficiency in this region. The mutation introduces a new Sau3A1 restriction site which allows polymerase chain reaction (PCR)-based diagnosis of this mutation that should be useful in diagnosis, carrier detection, and prenatal diagnosis. The presence of mental retardation and relative infrequency of skeletal fractures distinguish the clinical course of the patients with the Arabic mutation from those of the American and Belgian patients with the His 107-->Tyr mutation.
Using an improved method of gel electrophoresis, many hitherto unknown
proteins have been found in bacteriophage T4 and some of these have been
identified with specific gene products. Four major components of the
head are cleaved during the process of assembly, apparently after the
precursor proteins have assembled into some large intermediate
structure.
A series of mercaptoacyl amino acids and related compounds was synthesized and evaluated for inhibition of angiotensin-converting enzyme (ACE) in order to determine the nature and importance of the putative interaction between ACE and the amide moiety of inhibitors such as captopril (3-mercapto-2-methylpropanoyl-L-proline). It was concluded that the interaction involves a hydrogen bond from a donor site on ACE to the oxygen of the amide carbonyl. Compounds in which the amide moiety is replaced by other groups (ester, ketone, sulfonamide) capable of accepting a hydrogen bond are effective inhibitors, but compounds in which only the geometrical features of the amide are retained are ineffective inhibitors. The presence of an NH group is not necessary for effective inhibition. The activity of a series of mercaptoacyl cycloalkyl carboxylic acids parallels the activity of the isosteric series of mercaptoacyl imino acids.
The catalytic zinc ion of human carbonic anhydrase II (CAII) is coordinated by three histidine ligands (H94, H96, and H119) and a hydroxide ion with tetrahedral geometry. Structural and functional analysis of variants in which the zinc ligands H94 and H119 are substituted with asparagine and glutamine, and comparison with results obtained with aspartate and glutamate substitutions indicate that the neutral ligand field provided by the protein optimizes the electrostatic environment for the catalytic function of the metal ion, including stabilization of bound anions. This is demonstrated by catalytic activity measurements for ester hydrolysis and CO2 hydration, as well as sulfonamide inhibitor affinity assays. High-resolution X-ray crystal structure determinations of H94N, H119N, and H119Q CAIIs reveal that the engineered carboxamide side chains coordinate to zinc with optimal stereochemistry. However, zinc coordination geometry remains tetrahedral only in H119Q CAII. Metal geometry changes to trigonal bipyramidal in H119N CAII due to the addition of a second water molecule to the zinc coordination polyhedron and also in H94N CAII due to the displacement of zinc-bound hydroxide by the bidentate coordination of a Tris molecule. Possibly, the bulky histidine imidazole ligands of the native enzyme play a role in disfavoring trigonal bipyramidal coordination geometry for zinc. Protein-metal affinity is significantly compromised by all histidine --> carboxamide ligand substitutions. Diminished affinity may result from significant movements (up to 1 A) of the metal ion from its position in the wild-type enzyme, as well as the associated, minor conformational changes of metal ligands and their neighboring residues.
The development of new nonnucleoside inhibitors of human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT) active against the drug-induced mutations in RT continues to be a very important goal of AIDS research. We used a known inhibitor of HIV-1 RT, 1-(2,6-difluorophenyl)-1H,3H-thiazolo[3,4-alpha]benzimidazole (TZB), as the lead structure for drug design with the objective of making more potent inhibitors against both wild-type (WT) and variant RTs. A series of structurally related 1,2-substituted benzimidazoles was synthesized and evaluated for their ability to inhibit in vitro polymerization by HIV-1 WT RT. A structure-activity study was carried out for the series of compounds to determine the optimum groups for substitution of the benzimidazole ring at the N1 and C2 positions. The best inhibitor, 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methylbenzimida zole (35), has an IC50 = 200 nM against HIV-1 WT RT in an in vitro enzyme assay. Cytoprotection assays utilizing HIV-infected MT-4 cells revealed that 35 had strong antiviral activity (EC50 = 440 nM) against wild-type virus while retaining broad activity against many clinically observed HIV-1 strains resistant to nonnucleoside inhibitors. Overall, the activity of 35 against wild-type and resistant strains with amino acid substitution in RT is 4-fold or greater than that of TZB and is comparable to that of other nonnucleoside inhibitors currently undergoing clinical trials, most of which do not have the capacity to inhibit the variant forms of the enzyme.
Several 2-substituted alpha-D- and alpha-L-lyxofuranosyl and 5-deoxylyxofuranosyl derivatives of 5,6-dicholro-2-(isopropylamino)-1-(beta-L-ribofuranosyl) benzimidazole (1263W94) and 2,5,6-trichloro-1(beta-D-ribofuranosyl)benzimidazole (TCRB) were synthesized and evaluated for activity against two herpesviruses (HSV-1 and HCMV) and for their cytotoxicity against HFF and KB cells. Condensation of 1,2,3,5-tetra-O-acetyl-L-lyxofuranose (2a) with 2,5,6-trichlorobenzimidazole (1) yielded the alpha-nucleoside 3a. The 2-bromo derivative and 2-methylamino derivative were prepared by treatment of 3a with HBr followed by deprotection or from methylamine, respectively. Compound 3a was deprotected and the resultant nucleoside used to prepare the 2-cyclopropylamino and 2-isopropylamino derivatives. The 2-alkylthio nucleosides were prepared by condensing 2a with 5,6-dichlorobenzimidazole-2-thione followed by deprotection. Alkylation of this adduct gave the 2-methylthio and 2-benzylthio derivatives. Condensation of 5-deoxy-1,2,3-tri-O-acetyl-L-lyxofuranosyl, prepared from L-lyxose, with 1 or 2-bromo-5,6-dichlorobenzimidazole (15), followed by deprotection, gave the 2-chloro or 2-bromo-5'-deoxylyxo-furanosyl derivative, respectively. The cyclopropylamino derivative was prepared from the 2-chloro derivative. All D-isomers were prepared in an analogous fashion from D-lyxose. Either compounds were inactive against HSV-1 or weak activity was poorly separated from cytotoxicity. In contrast, the 2-halogen derivatives in both the alpha-lyxose and 5-deoxy-alpha-lyxose series were active against the Towne strain of HCMV. The 5-deoxy alpha-L analogues were the most active, IC50's = 0.2-0.4 microM, plaque assay; IC90's = 0.2-2 microM, yield reduction assay. All of the 2-isopropylamino or 2-cyclopropylamino derivatives were less active (IC50's = 60-100 microM, plaque assay; IC90's = 17-100 microM, yield reduction assay) and were not cytotoxic. The methylamino, thio, and methylthio derivatives were neither active nor cytotoxic. The benzylthio derivatives were weakly active, but this activity was poorly separated from cytotoxicity. The alpha-lyxose L-isomers were more active in a plaque assay against the AD169 strain of HCMV compared to the Towne strain, thereby providing additional evidence of antiviral specificity.
X-ray crystal structures of carbonic anhydrase II (CAII) complexed with sulfonamide inhibitors illuminate the structural determinants of high affinity binding in the nanomolar regime. The primary binding interaction is the coordination of a primary sulfonamide group to the active site zinc ion. Secondary interactions fine-tune tight binding in regions of the active site cavity >5 A away from zinc, and this work highlights three such features: (1) advantageous conformational restraints of a bicyclic thienothiazene-6-sulfonamide-1,1-dioxide inhibitor skeleton in comparison with a monocyclic 2,5-thiophenedisulfonamide skeleton; (2) optimal substituents attached to a secondary sulfonamide group targeted to interact with hydrophobic patches defined by Phe131, Leu198, and Pro202; and (3) optimal stereochemistry and configuration at the C-4 position of bicyclic thienothiazene-6-sulfonamides; the C-4 substituent can interact with His64, the catalytic proton shuttle. Structure-activity relationships rationalize affinity trends observed during the development of brinzolamide (Azopt), the newest carbonic anhydrase inhibitor approved for the treatment of glaucoma.
Donepezil is an effective, well-tolerated, and easily administered symptomatic treatment for mild-to-moderate Alzheimer disease (AD). Data from Phase III clinical trials have demonstrated that donepezil improves cognition, global function, and activities of daily living. In addition, there were no clinically significant treatment-related effects on vital signs or laboratory values in any trial. Adverse events, when present, were generally mild in intensity, transient, and resolved during continued treatment with donepezil. This favorable safety profile, together with its reported clinical benefits established donepezil as one standard of AD therapy. Vitamin E is one of two anti-oxidant therapies that may help to slow the progression of AD over at least a two-year period. One large-scale clinical trial suggests that it has sufficient benefit and safety to join donepezil as a current standard of AD therapy.
Hepatic impairment can alter the pharmacokinetic profiles of cardiovascular drugs, which can lead to unwanted toxicity. In the presence of cirrhosis, portosystemic shunting occurs and cytochrome P450 activity is reduced. Impaired oxygen uptake caused by changes in the liver's sinusoids, as proposed by the oxygen limitation theory, may also explain the alteration of drug metabolism seen in cirrhosis. With congestive heart failure, sinusoidal congestion and hypoperfusion of the liver are seen. Similar to cirrhosis, the common pathway for hepatic damage in congestive heart failure seems to be liver hypoxia, which may explain the disease's effect on drug metabolism. Since routine hepatic function tests do not always relate to the liver's ability to eliminate drugs, existing guidelines for dosing cardiovascular drugs in patients with hepatic impairment are limited. This article provides guidance for dosing cardiovascular drugs in cirrhotic and heart failure patients based on available research data. Altered drug metabolism, especially in congestive heart failure, tends to be overlooked or not realized in clinical practice. Therefore, further research is needed in congestive heart failure to better elucidate safe prescribing patterns.
The polyhalogenated benzimidazole nucleosides 2,5, 6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) and the 2-bromo analogue (BDCRB) were synthesized in our laboratory and established as potent and selective inhibitors of human cytomegalovirus (HCMV) with a novel mode of action. In an effort to study the behavior of the key substructure in a dimensionally extended manner and probe the spatial limitation of the target enzyme(s), a series of 2-substituted 6, 7-dichloro-1-(beta-D-ribofuranosyl)naphtho¿2,3-dĭmidazoles and the N1- and N3-ribonucleosides of 2-substituted 6,7-dichloroimidazo¿4, 5-bquinolines were prepared. The nucleosides 6, 7-dichloro-1-(beta-D-ribofuranosyl)imidazo¿4,5-bquinolin-2-one and 6,7-dichloro-3-(beta-D-ribofuranosyl)imidazo¿4,5-bquinolin-2-one were selected and used as the key synthetic intermediates in the imidazo¿4,5-bquinoline series. Evaluation of the compounds for activity against HCMV and herpes simplex virus type 1 revealed that the trichloro analogues of TCRB (2a, 3a) were nearly as active against HCMV as TCRB but were more cytotoxic. The results suggest that extending the heterocycle of TCRB affected the affinity for the HCMV target only slightly but increased the affinity for cellular enzymes.