Aminobenzoic Acid Derivatives Research Articles

ChemInform Abstract: Design, Synthesis and Biological Activity Evaluation of 2‐Mercapto‐4(3H)‐quinazolinone Derivatives as Novel Inhibitors of Protein Tyrosine Phosphatase 1B.

AbstractThe title derivatives are obtained by reaction of aminobenzoic acid with formamide/isothiocyanate or by reaction of 4‐substituted aminobenzoic acid derivatives (I) with phenyl isothiocyanate (II), followed by further derivatization.

Synthesis and cytotoxicity of some d-mannose click conjugates with aminobenzoic acid derivatives

Two sets of new conjugates obtained from d-mannose derivatives and o-, m-, and p-substituted benzoic acid esters interconnected through a triazole ring were synthesized by Cu(I) catalyzed azide–alkyne cycloaddition. All synthesized compounds were tested for their in vitro cytotoxic activity against seven cancer cell lines with/without multidrug resistance phenotype as well as non-tumor MRC-5 and BJ fibroblasts. Butyl ester of 4-aminobenzoic acid 6c showed the highest activity among all tested compounds, however, it was active only against K562 myeloid leukemia cells. N-Glycosyltriazole conjugates, both acetylated and nonacetylated at mannose moiety, were almost completely inactive. In contrast, some of the acetylated O-glycosyl conjugates showed cytotoxic activity which was cell line dependent and strongly affected by position of benzoic acid substitution as well as a length of its ester alkyl chain; the most potent compound was acetylated mannoside conjugated with octyl ester of m-substituted benzoic acid. However, deacetylation resulting in hydrophilicity increase of the glycosides almost completely abolished their cytotoxic potency.

Mutational Biosynthesis of Ansamitocin Antibiotics: A Diversity‐Oriented Approach to Exploit Biosynthetic Flexibility

New ansamitocin derivatives were prepared by feeding aminobenzoic acid derivatives to cultures of Actinosynnema pretiosum HGF073, a mutant strain blocked in the biosynthesis of the required 3-amino-5-hydroxybenzoic acid (AHBA) starter unit. Use of several aminobenzoic acids as precursors led to a spectrum of products, reflecting the sequence of post-PKS tailoring steps involved in the generation of ansamitocins and adding novel aspects to the published suggestion model of post-PKS tailoring logic and flexibility. The studies provide insights into the substrate flexibility of the enzymes required for ansamitocin biosynthesis in A. pretiosum, whereas preliminary biological testing of the derivatives isolated and fully characterized by NMR spectroscopy allowed structure-activity relationship assignments to be made for a variety of intermediates occurring during the post-PKS tailoring sequence in ansamitocin biosynthesis.

Synthesis of oxo-Phosphoranylidene Aminobenzoic Acid Derivatives by a Multicomponent Reaction

2-Aminobenzoic acids or 4-aminobenzoic acid react with dimethyl acetylenedicarboxylate/triphenylphosphine in less than 20 min at 15–25°C to produce new organic phosphorus compounds in good to excellent yields. The conversion occurs with selective N- over O-alkylation of the amino group and isolation of the products is accomplished simply by filtration.

Discovery of novel inhibitors for DHODH via virtual screening and X-ray crystallographic structures

Amino-benzoic acid derivatives 1– 4 were found to be inhibitors for DHODH by virtual screening, biochemical, and X-ray crystallographic studies. X-ray structures showed that 1 and 2 bind to DHODH as predicted by virtual screening, but 3 and 4 were found to be structurally different from the corresponding compounds initially identified by virtual screening.

Experimental and computational study on the aqueous acidity constants of some new aminobenzoic acid compounds

The acidity constants of three new aminobenzoic acid derivatives were determined using potentiometric and spectrophotometric methods in 0.10 M aqueous potassium nitrate solution as supporting electrolyte. The potentiometric data and UV–Vis absorption spectra of solutions were recorded in the course of their pH-metric titration with a standard base solution. The protolytic equilibrium constants, concentration distribution diagrams and number of components involved have been calculated. The relative p K a values for three acids were also calculated using ab initio quantum mechanical method at the HF/6-31G** level of theory in combination with CPCM continuum solvation method. The influence of substituents on the ionization constants of the studied molecular structures was investigated. The satisfactory agreement between the experimentally derived and theoretically calculated p K a values provides solid support for the acid–base reactions proposed in this work.

Docking of oxalyl aryl amino benzoic acid derivatives into PTP1B

Protein Tyrosine Phosphatases (PTPs) that function as negative regulators of the insulin signaling cascade have been identified as novel targets for the therapeutic enhancement of insulin action in insulin resistant disease states. Reducing Protein Tyrosine Phosphatase1B (PTP1B) abundance not only enhances insulin sensitivity and improves glucose metabolism but also protects against obesity induced by high fat feeding. PTP1B inhibitors such as Formylchromone derivatives, 1, 2-Naphthoquinone derivatives and Oxalyl aryl amino benzoic derivatives may eventually find an important clinical role as insulin sensitizers in the management of Type-II Diabetes and metabolic syndrome. We have carried out docking of modified oxalyl aryl amino benzoic acid derivatives into three dimensional structure of PTP1B using BioMed CAChe 6.1. These compounds exhibit good selectivity for PTP1B over most of phosphatases in selectivity panel such as SHP-2, LAR, CD45 and TCPTP found in literature. This series of compounds identified the amino acid residues such as Gly220 and Arg221 are important for achieving specificity via H-bonding interactions. Lipophilic side chain of methionine in modified oxalyl aryl amino benzoic acid derivative [1b (a2, b2, c1, d)] lies in closer vicinity of hydrophobic region of protein consisted of Meth258 and Phe52 in comparison to active ligand. Docking Score in [1b (a2, b2, c1, d)] is -131.740Kcal/mol much better than active ligand score -98.584Kcal/mol. This information can be exploited to design PTP1B specific inhibitors.

Photocatalytic degradation of Michler's Ethyl Ketone in titanium dioxide dispersions under UV irradiation

Michler's Ethyl Ketone (MEK) can be degraded photocatalytically under UV irradiation in aqueous dispersions. In the presence of both UV light illumination and TiO 2 catalyst, MEK was more effectively degraded than with either UV or TiO 2 alone. Results obtained show rapid and complete oxidation of MEK after 20-h, and more than 94% of the MEK was mineralized after a 48-h exposure to UV-365 nm irradiation. To obtain a better understanding on the mechanistic details of this TiO 2-assisted photodegradation of the MEK with UV irradiation, 19 intermediates of the process were separated, identified, and characterized by HPLC-ESI-MS and GC–MS techniques in this study. The analytical results indicated that the photocatalytic degradation of MEK yielded intermediates such as N-hydroxyethylated species, N-de-ethylated compounds, aminobenzoic acid derivatives, aminobenzene derivatives, and aliphatic products. The possible degradation pathways were proposed and discussed on the basis of the evidence of oxidative intermediate formation. The reaction mechanisms of TiO 2/UV proposed in this research should prove useful in future efforts to breakdown the organic compounds in wastewater.

P–Aminobenzoic acid derivatives as acetylcholinesterase inhibitors

Because Alzheimer's disease (AD) is a medical problem characterized by progressive loss of memory and cognition that is associated with a deficient cholinergic system, this work aims to evaluate some p-aminobenzoic acid (PABA) derivatives as acetylcholinesterase inhibitors in vitro, in continuation with our last studies. The assayed compounds are low toxic, simple-structured and low cost.

Improved loading and cleavage methods for solid-phase synthesis using chlorotrityl resins: synthesis and testing of a library of 144 discrete chemicals as potential farnesyltransferase inhibitors.

The use of chlorotrityl resins for the immobilization of amines is sometimes deterred by the lengthy process of loading the reactants on the resins and product decomposition caused by the reactive chlorotrityl group in the presence of 1% TFA as a cleavage agent. Here, we report improved methods developed for selective and efficient loading of aminobenzoic acid derivatives on chlorotrityl resins and for cleavage of aniline-containing products from the resins without decomposition. These methods led to the synthesis of a library of 144 discrete chemicals as potential farnesyltransferase inhibitors (FTIs) using IRORI's radio-frequency-encoded sorting technique and to the study of the applicability of the bivalence approach to the development of FTIs.

Synthesis, Anticholinesterase Activity and Structure—Activity Relationships of m‐Aminobenzoic Acid Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Determination of some aminobenzoic acid derivatives: glafenine and metoclopramide

Simple, sensitive and accurate spectrophotometric methods for the determination of glafenine and metoclopramide hydrochloride are described. The first method is based on the oxidation of glafenine with iodic acid in strong acid medium to give a coloured diphenylbenzidine derivative and subsequent measurement of the coloured product at 509 nm. Beer's law is obeyed over the concentration range 2.5–20 μg ml −1. The second method depends on the interaction of metoclopramide hydrochloride with p-dimethylaminocinnamaldehyde, to give a red coloured schiff's base with an absorbance maximum at 548 nm. Obedience to Beer's law is achieved over the concentration range 5–30 μg ml −1. First-derivative method is used to overcome the slight interference of p-dimethylaminocinnamaldehyde reagent blank at the wavelength of measurement. Linearity between the peak heights at 576 nm versus concentration range 5–25 μg ml −1 metoclopromide hydrochloride is obtained. The proposed methods have been successfully applied to the determination of these drugs in commercial products without interference. The validity of the methods is assessed by applying the standard addition technique, the relative standard deviation is less than 1%. The proposed methods are compared with reference methods with good agreement.

Contact Sensitization to Sunscreens

Background: Para aminobenzoic acid (PABA) derivatives and cinnamate are chemical sunscreens that protect against UVB (290 to 320 nm). They may occasionally produce contact and photocontact sensitization. Objective: To report a sensitization to octyldimethyl-PABA and photosensitization to 2-ethylhexylp-metossicinnamate in a 31-year-old man. Methods: A patient with a 3-year history of a relapsing dermatitis involving the face, neck, legs, and knees is reported. The eruption had recurred every summer after sunlight exposure. Patch tests with International Contact Dermatitis Research Group (IC-DRG) standard series and the photopatch series (Hermal-Trolab, Reinbek, Germany) using Finn chambers on Scanpor (Norgesplaster A/S, Oslo, Norway) were carried out. Results: We found a positive reaction to Balsam of Peru, fragrance mix, Escalol 507, and Parsol MCX (Hermal-Trolab, Reinbek, Germany). Photopatch test revealed a positive reaction only for Parsol MCX. Conclusion: The incidence of allergic contact dermatitis to sunscreens is considered low. Recently sunscreens patch test concentrations have been increased from 2% to 10%. These higher percentages will probably permit the identification of more cases of sunscreens allergy in the near future.

Contact sensitization to sunscreens

Background : Para aminobenzoic acid (PABA) derivatives and cinnamate are chemical sunscreens that protect against UVB (290 to 320 nm). They may occasionally produce contact and photocontact sensitization. Objective : To report a sensitization to ocytl-dimethyl-PABA and photosensitization to 2-ethylhexyl-p-metossicinnamate in a 31-year-old man. Methods : A patient with a 3-year history of a relapsing dermatitis involving the face, neck, legs, and knees is reported. The eruption had recurred every summer after sunlight exposure. Patch tests with International Contact Dermatitis Research Group (IC-DRG) standard series and the photopatch series (Hermal-Trolab, Reinbek, Germany) using Finn chambers on Scanpor (Norgesplaster A/S, Oslo, Norway) were carried out. Results : We found a positive reaction to Balsam of Peru, fragrance mix, Escalol 507, and Parsol MCX (Hermal-Trolab, Reinbek, Germany). Photopatch test revealed a positive reaction only for Parsol MCX. Conclusion : The incidence of allergic contact dermatitis to sunscreens is considered low. Recently sunscreens patch test concentrations have been increased from 2% to 10%. These higher percentages will probably permit the identification of more cases of sunscreens allergy in the near future.

Studies of Reactive Inorganic Layered Compounds with Drugs. Part IV. A New Ultraviolet Protective Agent of the Intercalation Compound of Aminobenzoic Acid Esters (UV Absorber) and Synthetic Mica (Inorganic Layered Compound).

The interaction between a sodium-type synthetic mica (Na-TSM), a material of reactive layered compounds which exhibit characteristic light scattering, and some aminobenzoic acid derivatives which act as UV absorbing agents (UV absorber), was investigated. Due to the observed elongation of interlayer spacing (increase in the d-value) by X-ray diffraction analysis, it was found that the powdered form of 4-aminobenzoic acid ethyl ester (4-ABE) interacts with Na-TSM, and can be immobilized in the interlayer space of Na-TSM. Consequently, an intercalation compound of 4-ABE and Na-TSM was obtained. The formation of the intercalation compound of 4-ABE and Na-TSM was accelerated by heat processing, particularly at temperatures exceeding the melting point of 4-ABE. When 2-aminobenzoic acid methyl ester (2-ABM) in liquid form at room temperature was used instead of 4-ABE, the intercalation compound of 2-ABM and Na-TSM was formed in a similar manner to that of 4-ABE and Na-TSM. The heat processing again accelerated the formation of the intercalation compound of 2-ABM and Na-TSM. Interestingly, a difference in the formation behavior of intercalation compounds between 4-ABE and 2-ABM was observed. The intercalation compound of Na-TSM and 4-ABE or 2-ABM showed efficient UV absorption in the UV B and UV A wavelength regions. Therefore, application of a layered compound of Na-TSM and 4-ABE or 2-ABM as a novel UV screening system is promising.

A Non-peptide Mimetic of Ras-CAAX: Selective Inhibition of Farnesyltransferase and Ras Processing

Cysteine farnesylation of the carboxyl-terminal tetrapeptide CAAX (C = Cys, A = Leu, Ile, or Val, X = Met or Ser) of the oncogene product Ras is required for its malignant transformation activity. As a consequence farnesyltransferase (FTase), the enzyme responsible for this lipid modification, has become one of the most sought-after targets for anticancer drug development. We have recently designed peptide mimics of the COOH-terminal Cys-Val-Ile-Met of KB-Ras where the dipeptide Val-Ile was replaced by aminobenzoic acid derivatives. Although these peptidomimetics are potent inhibitors of FTase in vitro, they retain several undesirable peptide features that hamper their use in vivo. We report here the design, synthesis, and biological activity of the first non-peptide mimetics of CAAX where the tripeptide AAX was replaced by biphenyl derivatives. (R)-4-[N-(3-mercapto-2-aminopropyl)]amino-3'- carboxybiphenyl, where the cysteine is linked to the biphenyl derivative through a secondary amine, contains no amino acids, lacks peptidic features, and has no hydrolyzable bonds. This peptidomimetic is a potent inhibitor of FTase in vitro (IC50 = 50-150 nM) and disrupts Ras processing in whole cells. Furthermore, this non-peptide mimetic of CAAX is highly selective for FTase (666-fold) relative to the closely related geranylgeranyltransferase I. This selectivity is also respected in vivo since the processing of Ras but not the geranylgeranylated Rap1A was disrupted in whole cells. Structure activity relationship studies revealed that FTase recognition and inhibitory potency of CAAX peptidomimetics require free thiol and carboxylate groups separated by a hydrophobic moiety, and that precise positioning of these functional groups must correspond to that of the parent CAAX. The true CAAX peptidomimetic described in this manuscript has several desirable features for further development as a potential anticancer agent. It is not metabolically inactivated by FTase, does not require a pro-drug strategy for inhibition in vivo, and is selective for farnesylation relative to geranylgeranylation.

Capillary zone electrophoresis of p‐aminobenzoic acid derivatives of aldoses, ketoses and uronic acids

Aldoses, ketoses and uronic acids were derivatized with p-aminobenzoic acid and separated as their borate complexes by capillary zone electrophoresis, using a capillary tube of fused silica containing 150 mM borate buffer, pH 10.0, as carrier. The electrophoretic mobilities of 22 carbohydrates were determined and found to increase with increasing stability of the borate complexes formed. Besides the number of hydroxyl groups and the presence of substituents, complex stability depended most strongly on the configuration of the three vicinal hydroxyl groups at C2, C3 and C4. On-column UV monitoring at 285 nm allowed the detection of glucose with a lower mass detection limit of 15 fmol and a concentration sensitivity of 4 microM. Reproducible quantification of carbohydrates was achieved at least in the concentration range of 0.1-10 mM in reaction solutions by the relative peak area method, using cinnamic acid as internal standard. The method was applied successfully to the determination of the monosaccharide composition of polysaccharides extracted from Radix althaeae.

Rate constants for the reaction of singlet oxygen with derivatives of p-aminobenzoic acid

Summary p-Aminobenzoic acid and its derivatives are often topically applied to prevent damage to the skin by actinic radiation. It has recently been suggested that reaction of these compounds with photochemically generated singlet oxygen may contribute to the protective effect. The total rate constants for interaction (reaction plus quenching) of several p -aminobenzoic acid derivatives with singlet oxygen have been determined in chloroform. The low rate constants for interaction, ethyl p -aminobenzoate, 8 × 104M−1s−1 ethyl p-N, N-dimethylaminobenzoate, 5.5 × 106M−1s−1, and p-N,N-dimethylaminobenzaldehyde, 1.1 × 106M−1s−1, indicate that interaction with singlet oxygen is not an important mode of protection for these compounds.

Zwitterion ratios of aminobenzoic acids

Relations have been established between the pKa values for the non- zwitterionic forms of meta- and para-aminobenzoic acids, pKB, and the pKa values of the corresponding methyl and ethyl esters, pKE. For methyl m-aminobenzoate, the expression is pKB = pKE + 0.09, whilst for the ethyl ester it is pKB = pKE + 0.03. The corresponding relations for p- aminobenzoic acid derivatives are pKB = pKE + 0.06 for the methyl ester, and pKB = pKE + 0.03 for the ethyl ester. The mioroscopic constants pertaining to the zwitterionic equilibria are given, and are used to establish the Hammett substituent constants, σm, for the following meta substituent groups: NH2, 0.00; NH3+, 0.98; NHCH2COOEt, -0.10; COOH, 0.30; COOMe, 0.33; COOEt, 0.31; COO-, 0.01.

Separation of p-aminobenzoic acid derivatives by paper chromatography.

Separation of p-aminobenzoic acid derivatives by paper chromatography.