Showing papers by "Alan R. Katritzky published in 2009"
TL;DR: Fifteen 2-aryl 5-(4-oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl)furans were synthesized by Suzuki-Miyaura cross-coupling followed by a Knoevenagel condensation and tested for their anti-HIV-1 activity and cytotoxicity on MT-2 cells, suggesting that these compounds can serve as leads for development of novel small molecule HIV fusion inhibitors.
Abstract: We previously identified two small molecules targeting the HIV-1 gp41, N-(4-carboxy-3-hydroxy)phenyl-2,5-dimethylpyrrole 12 (NB-2) and N-(3-carboxy-4-chloro)phenylpyrrole 13 (NB-64), that inhibit HIV-1 infection at low micromolar levels. On the basis of molecular docking analysis, we designed a series of 2-aryl 5-(4-oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl)furans. Compared with 12 and 13, these compounds have bigger molecular size (437-515 Da) and could occupy more space in the deep hydrophobic pocket on the gp41 NHR trimer. Fifteen 2-aryl 5-(4-oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl)furans (11a-o) were synthesized by Suzuki-Miyaura cross-coupling followed by a Knoevenagel condensation and tested for their anti-HIV-1 activity and cytotoxicity on MT-2 cells. We found that all 15 compounds had improved anti-HIV-1 activity and 3 of them (11a, 11b, and 11d) exhibited inhibitory activity against replication of HIV-1(IIIB) and 94UG103 at <100 nM range, more than 20-fold more potent than 12 and 13, suggesting that these compounds can serve as leads for development of novel small molecule HIV fusion inhibitors.
100 citations
TL;DR: This perspective highlights interesting aspects of fluorescent labeling by fluorescent peptides and small organic fluorophores that can be incorporated into proteins by genetic fusion to produce a fluorescent label.
Abstract: Fluorescent labeling is today of paramount importance to biological studies and numerous chemical dyes are used extensively to label biological specimens. This perspective highlights interesting aspects of fluorescent labeling by fluorescent peptides and small organic fluorophores that can be incorporated into proteins by genetic fusion to produce a fluorescent label. While many fluorescence applications rely on the use of intrinsic fluorophores, the development of new extrinsic fluorophores remains an essential element for the design of new fluorescent probes.
74 citations
TL;DR: The developed methodology allows simple solution- and solid-phase preparative techniques to generate complex peptides and peptide conjugates and serves as a platform for generating diverse medicinal chemistry building block libraries involving amino acid and heterocyclic moieties crucial for drug development.
Abstract: N-(Protected α-aminoacyl)benzotriazoles are efficient intermediates for N- and O-aminoacylation. These intermediates enable fast preparations of biologically relevant peptides and peptide conjugates in high yields and purity, under mild reaction conditions, with full retention of the original chirality. The developed methodology allows simple solution- and solid-phase preparative techniques to generate complex peptides and peptide conjugates and serves as a platform for generating diverse medicinal chemistry building block libraries involving amino acid and heterocyclic moieties crucial for drug development. 1 Introduction 1.1 Background to Peptide Synthesis 1.2 Preparation of N-(Protected α-Aminoacyl)benzotriazoles 2 Peptide Coupling with Chiral N-(Protected α-Amino-acyl)benzotriazoles 2.1 Preparation of Dipeptides 2.2 Preparation of Tripeptides 2.2.1 Tripeptides by the Fragment-Coupling Procedure 2.2.2 Peptides by the Stepwise-Coupling Procedure 2.3 Preparation of Dipeptides Involving Sterically Hindered Amino Acids 2.4 Microwave-Assisted Solid-Phase Peptide Synthesis Utilizing N-(Protected α-Aminoacyl)benzotriazoles 3 Other N-Acylations Using Benzotriazole-Activated Intermediates 3.1 Glyco-Amino-Acids and Glycopeptides 3.2 Fluorescent Amino Acids and Peptides 3.3 Monosaccharide-Based Water-Soluble Fluorescent Tags 3.4 Chiral Peptide Nucleic Acid (PNA) Monomers with Modified Backbones 3.5 Heterocyclic Amines 4 O-Aminoacylation with Chiral N-(Protected α-Aminoacyl)benzotriazoles 4.1 Steroid Esters of α-Amino Acids 4.2 Terpene Esters of α-Amino Acids and Esters Derived from Long-Chain Alcohols 4.3 O-(Aminoacyl)sugar Conjugates 5 Conclusion.
44 citations
TL;DR: The experimental EC50 toxicities toward Daphnia magna for a series of 130 benzoic acids, benzaldehydes, phenylsulfonyl acetates, cycloalkane-carboxylates, benzanilides, and other esters were studied using the Best multilinear regression algorithm implemented in CODESSA to demonstrate the high robustness of the model proposed.
Abstract: The experimental EC(50) toxicities toward Daphnia magna for a series of 130 benzoic acids, benzaldehydes, phenylsulfonyl acetates, cycloalkane-carboxylates, benzanilides, and other esters were studied using the Best multilinear regression algorithm (BMLR) implemented in CODESSA. A modified quantitative structure-activity relationships (QSAR) procedure was applied guaranteeing the stability and reproducibility of the results. Separating the initial data set into training and test subsets generated three independent models with an average R(2) of .735. A five-descriptor general model including all 130 compounds, constructed using the descriptors found effective for the independent subsets, was characterized by the following statistical parameters: R(2) = .712; R(2)(cv) = .676; F = 61.331; s(2) = 0.6. The removal of two extreme outliers improved significantly the statistical parameters: R(2) = .759; R(2)(cv) = .728; F = 77.032; s(2) = 0.499. The sensitivity of the general model to chance correlations was estimated by applying a scrambling procedure involving 20 randomizations of the original property values. The resulting R(2) = .192 demonstrated the high robustness of the model proposed. The descriptors appearing in the obtained models are related to the biochemical nature of the adverse effects. An additional study of the EC(50)/LC(50) relationship for a series of 28 compounds (part of our general data set) revealed that these endpoints correlated with R(2) = .98.
38 citations
TL;DR: Structures 7b, 7d and 8b, 8d are supported by 2D NMR spectroscopic methods including gDQCOSY, g HMQC, gHMBC, and (1)H-(15)N CIGAR-gHMBC experiments and the structure of compound 8d was also supported by single-crystal X-ray diffraction.
Abstract: N-(Acyl)-1H-benzotriazoles 6a−f react with l-cysteine 5 at 20 °C to give exclusively (i) N-acyl-l-cysteines 8a−e in the presence of triethylamine in CH3CN−H2O (3:1), but (ii) S-acyl-l-cysteines 7a−e in CH3CN−H2O (5:1) in the absence of base. Structures 7b, 7d and 8b, 8d are supported by 2D NMR spectroscopic methods including gDQCOSY, gHMQC, gHMBC, and 1H−15N CIGAR-gHMBC experiments. The structure of compound 8d was also supported by single-crystal X-ray diffraction.
37 citations
TL;DR: In this paper, the relative reactivities of a series of polycyclic carbo-and heteroaromatic compounds to sulfonation by sulfur trioxide in nitrobenzene were measured and discussed.
31 citations
TL;DR: Extension to the syntheses of Leu-enkephalin and amyloid-beta demonstrates that this strategy comprises an efficient route to new and known "difficult" peptides.
Abstract: Microwave-assisted solid-phase syntheses of six “difficult” peptides, H-VVSVV-NH2 (3), H-VVVSVV-NH2 (4), H-VIVIG-OH (5), H-TVTVTV-NH2 (6), H-VKDGYI-NH2 (7), and H-VKDVYI-NH2 (8), were achieved util...
27 citations
TL;DR: N-( pg-alpha-aminoxy acids) 1a-g are converted to N-(Pg-alpha -aminoxyacyl)benzotriazoles 2a-G, which react under mild conditions with amines, alpha-amino acids/alpha-dipeptides, and alpha-amin oxygen acids to give aminoxyacyL amides 3a- g, (3e+3e'), and (3g+3g').
Abstract: N-(Pg-α-aminoxy acids) 1a−g are converted to N-(Pg-α-aminoxyacyl)benzotriazoles 2a−g, which react under mild conditions with amines, α-amino acids/α-dipeptides, and α-aminoxy acids to give aminoxyacyl amides 3a−g, (3e+3e′), and (3g+3g′), aminoxy hybrid peptides 4a−h, (4a+4a′), 6a−d, 9a−e, (9a+9a′), and (9b+9b′), and α-aminoxy peptides 10a,b in good yields without racemization.
27 citations
TL;DR: Ddl‐Ibuprofen and l‐naproxen were coupled with amino acids and other bioactive compounds to provide ibuproen and naproxen bioconjugates in 61–95% yield as prodrugs or potential drug candidates.
Abstract: dl-Ibuprofen and l-naproxen were coupled with amino acids and other bioactive compounds to provide ibuprofen and naproxen bioconjugates in 61–95% yield as prodrugs or potential drug candidates.
27 citations
TL;DR: The QSPR models (linear and nonlinear) for the first CMC in this work could provide useful predictions of the CMC of structurally similar cationic surfactants.
25 citations
TL;DR: Several series of novel compounds have been prepared containing dicyanomethylidene groups including 1-alkyl-3-dicy-methyl-deneindol-2-ones and 6,6dicyanofulvenes as discussed by the authors.
TL;DR: In this article, Boltorn® H20, Boltorn H30, and BoltornH40 were endcapped with azido and activated acetylenic groups in good to excellent yields (75-95%) following an acid catalyzed procedure.
Abstract: Second-, third-, and fourth-generation hyperbranched aliphatic polyols namely Boltorn® H20, Boltorn H30, and Boltorn H40 were endcapped with azido and activated acetylenic groups in good to excellent yields (75–95%) following an acid catalyzed procedure. The resultant terminally functionalized dendritic azido and acetylenic groups undergo 1,3-dipolar cycloaddition using methyl (or ethyl) propiolate and benzyl azide, respectively, under catalytic or noncatalytic conditions below 40 °C to yield 1,2,3-triazole dendrimeric polymers in 82–95% yield, under extremely mild conditions that could be applied for compounds sensitive to acid, base, or heat. The dendritic azido and activated acetylenic derivatives may act as novel scaffolds to tune the mechanical properties of different polymers. © 2009 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 47: 3748–3756, 2009
TL;DR: 2H-Chromene-based conjugates of N-acyl-1,omega-amino acids of natural amino acids and of dipeptide are prepared by N-ACYlbenzotriazole methodology by generalized with respect to an increase or decrease in the chain length of the spacer.
Abstract: 2H-Chromene-based conjugates of N-acyl-1,ω-amino acids (5, 9a−f, 14a−f) of natural amino acids (10a,b) and of dipeptide (10c) are prepared (60−97%) by N-acylbenzotriazole methodology in aqueous media at 20 °C. Gelation properties of the corresponding sodium salts in DMF and DMSO are generalized with respect to an increase or decrease in the chain length of the spacer.
TL;DR: 2-Hydrazono-3-phenylquinazolin-4(3H)-ones 11a-i are shown by (15)N NMR to exist in DMSO solution predominantly as the imino tautomer B and not the amino tautomers A.
Abstract: 2-Hydrazono-3-phenylquinazolin-4(3H)-ones 11a-i are shown by (15)N NMR to exist in DMSO solution predominantly as the imino tautomers B and not the amino tautomers A. 2-Hydrazino-benzimidazole derivative 12 and 2-hydrazino-4,6-dimethylpyrimidine derivative 13 were found to exist predominantly as the amino tautomers.
TL;DR: A "universal solvation equation" (USE) available for the accurate estimation of desolvation energies in protein-ligand docking, for the prediction of many physical and ADMET properties, and for studying fluid phase equilibria.
Abstract: Theoretical quantifications of hydrogen bonding (HB) basicities and acidities, originally developed for aliphatic systems (J. Chem. Inf. Comput. Sci. 2004, 44, 1042−1055), are now extended to cover aromatic, heterocyclic, anionic, cationic and zwitter-ionic molecular fragments, thus encompassing a majority of druggable chemical space. The addition of terms accounting for cavity formation, polarity, hydrophobicity, and resonance allowed us to derive a new equation able to predict accurately free energies of solvation of diverse solutes, interphase transfers, and aqueous solubilities (log Sw). We thus provide a “universal solvation equation” (USE) available for the accurate estimation of desolvation energies in protein−ligand docking, for the prediction of many physical and ADMET properties, and for studying fluid phase equilibria.
TL;DR: The synthesis, cation binding and transmembrane conductive properties of a novel synthetic ion channel containing a redox-active ferrocene unit are described and it is revealed that this compound functioned effectively as an ion channel for both Na(+) and K(+).
Abstract: The synthesis, cation binding and transmembrane conductive properties of a novel synthetic ion channel containing a redox-active ferrocene unit are described. Fluorescence spectroscopy was used to demonstrate that the channel supports multiple ion coordination and association constants for 1:1 and 1:2 (channel:cation) coordination for both Na(+) and K(+) were evaluated. Experiments using a black lipid membrane preparation revealed that this compound functioned effectively as an ion channel for both Na(+) and K(+). Concomitant (23)Na NMR spectroscopy studies supported this finding and revealed a Na(+) flux, at least 5 times higher than ion transport rates by monensin. Furthermore, oxidation of the redox-active centre (Fe(2+) to Fe(3+)) effectively inhibited ion transport.
TL;DR: N-protected LL-dipeptide alcohols 3a-p, diastereomeric mixture (3d + 3d') and tripeptidealcohols 6a-c were synthesized by treatment of various amino alcohols with N-protected(alpha-aminoacyl)benzotriazoles 5a, 5b respectively in good yields with complete retention of chirality.
Abstract: N -Protected LL-dipeptide alcohols 3a–p, diastereomeric mixture (3d + 3d′) and tripeptide alcohols 6a–c were synthesized by treatment of various amino alcohols with N-protected(α-aminoacyl)benzotriazoles 1a–c, 1f–m, (1a + 1a′) and N-protected(α-dipeptidoyl)benzotriazoles 5a, 5b respectively in good yields with complete retention of chirality.
TL;DR: Optically pure conjugates of quinolone antibiotics with naturally occurring amino acids are synthesized in 40-98% yields.
Abstract: Optically pure conjugates of quinolone antibiotics with naturally occurring amino acids are synthesized in 40–98% yields.
TL;DR: In this article, the authors highlight interesting aspects of fluorescent labeling by fluorescent peptides and small organic fluorophores that can be incorporated into proteins by genetic fusion to produce a fluorescent label.
Abstract: Fluorescent labeling is today of paramount importance to biological studies and numerous chemical dyes are used extensively to label biological specimens. This perspective highlights interesting aspects of fluorescent labeling by fluorescent peptides and small organic fluorophores that can be incorporated into proteins by genetic fusion to produce a fluorescent label. While many fluorescence applications rely on the use of intrinsic fluorophores, the development of new extrinsic fluorophores remains an essential element for the design of new fluorescent probes.
TL;DR: In this article, N-(4-Arylazobenzoyl)-1H-benzotriazoles react with hydroxyterpenes, sugars, and steroids in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature in tetrahydrofuran to afford azo dye labeled terpenes and steroids (45-82% yield).
Abstract: N-(4-Arylazobenzoyl)-1H-benzotriazoles react with hydroxyterpenes, sugars, and steroids in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature in tetrahydrofuran to afford azo dye labeled terpenes, sugars, and steroids (45-82% yield).
TL;DR: Novel products were characterized by NMR and elemental analysis and dye‐labelled nucleosides obtained in 30–79% (average 45%) yields by treating N‐(4‐arylazobenzoyl)‐1H‐benzotriazoles 3a–b with appropriate nucleoside.
Abstract: Dye-labelled nucleosides were obtained in 30-79% (average 45%) yields by treating N-(4-arylazobenzoyl)-1H-benzotriazoles 3a-b with appropriate nucleosides. Similarly, 3a-b afforded dye-labelled threoninol conjugates in 55-89% (average 67%) yields. All novel products were characterized by NMR and elemental analysis.
TL;DR: N‐(4‐Arylazobenzoyl)‐1H‐benzotriazoles 15a, 15b react with dipeptides 12a–d, (12d+12d′) and tripeptide 14a, 14b to give azodye labeled‐dipeptides (16a–e, (16d+16d′), (16e+16e′), and ‐tri peptides 16
Abstract: N-(4-Arylazobenzoyl)-1H-benzotriazoles 15a, 15b react with dipeptides 12a-d, (12d+12d') and tripeptides 14a, 14b to give azodye labeled-dipeptides (16a-e), (16d+16d'), (16e+16e') and -tripeptides 16f, 16g in high yields (73-93%) with retention of chirality.
TL;DR: In this paper, the authors reported the acylation of sulfonamides with stable, crystalline N-(α,β-unsaturated acyl)benzotriazoles to give N-(β-unsaturated)sulfonamide.
Abstract: N-(α,β-Unsaturated acyl)sulfonamides are prepared (i) by the N-acylation of sulfonamides with N-(α,β-unsaturated acyl)benzotriazoles in the presence of potassium tert-butoxide or sodium hydride and (ii) by reactions of appropriate α,β-unsaturated carboxamides with sulfonylbenzotriazoles in the presence of sodium hydride. Published preparations of N-(α,β-unsaturated acyl)sulfonamides include (i) the acylation of sulfonamides (RSO2NH2) by (a) unsaturated acyl chlorides (R'CH=CHCOCl) in the presence of a base (such as triethylamine, 3,5a n-butyllithium, 4d or NaH 6,7 ) or a copper powder catalyst; 8 (b) unsaturated carboxylic acids via mixed anhydride in the presence of Lewis acid catalyst; 9 (ii) reactions of aryl isocyanates (RSO2NCO) with 1-alkenyltrialkylstannanes, di-1- alkenyldibutylstannanes in the presence of aluminium trichloride 10a or with substituted alkenes; 10b (iii) reactions of sulfonamide with the Wittig adduct obtained from (triphenylphosphoranylidene)ketene and an aldehyde; 11 (iv) coupling of unsaturated acids with sulfonamides in the presence of 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide (EDCI); 2,3,12 (v) dehydrogenation of the corresponding saturated analogs by using LDA followed by N-tert- butylbenzenesulfinimidoyl chloride. 5a,13 Herein, we report the acylation of sulfonamides with stable, crystalline N-(α,β-unsaturated acyl)benzotriazoles to give N-(α,β-unsaturated acyl)sulfonamides.
TL;DR: Quantitative structure-activity (property) relationships (QSA(P)R) as mentioned in this paper ) relate physical, chemical, physico-chemical, technological and biological properties of compounds to their structure.
Abstract: The establishment of quantitative relationships between numerous molecular properties and chemical structures is now of great importance to society in understanding and improving environmental, medicinal and technological aspects of life. Quantitative structure-activity (property) relationships (QSA(P)R) relate physical, chemical, physico-chemical, technological and biological properties of compounds to their structure. A major factor driving the widespread use of QSP(A)R models is the rational estimation of properties of new compounds, without first synthesizing and testing them. Some of our recent findings in the field are briefly discussed below.
TL;DR: In this article, the best multiple linear regression (BMLR) method implemented in CODESSA was used to build multiparameter linear QSPR models and select set of descriptors for further treatment by the SVM and PPR.
Abstract: Correlation of gas-phase lithium cation basicities (LCB) of 259 diverse compounds extends the published datasets utilizing multilinear, support vector machine (SVM) and projection pursuit regression (PPR) modeling. The best multiple linear regression (BMLR) method implemented in CODESSA was used to: (i) build multiparameter linear QSPR models and (ii) select set of descriptors for further treatment by the SVM and PPR. The external predictivity and the performance of each of the above methods was estimated and compared to those of the other techniques. The PPR method produced results superior to SVM, which in turn out-performed MLR. The physico-chemical interpretation of each of the descriptors provides new insight into the mechanism of LCB interactions.
TL;DR: In this paper, 1.5-(Substituted amino)-1,2,3,4,4thiatriazoles 15a-15i were conveniently synthesized in 73-97% yields in a one-pot procedure from bis(1 H -benzotriazol-1-yl)methanethione and amines.
Abstract: 5-(Substituted amino)-1,2,3,4-thiatriazoles 15a – 15i were conveniently synthesized in 73–97% yields in a one-pot procedure from bis(1 H -benzotriazol-1-yl)methanethione and amines.
TL;DR: In this article, N-(4-Arylazobenzoyl)-1H-benzotriazoles react with hydroxyterpenes, sugars, and steroids in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature in tetrahydrofuran to afford azo dye labeled terpenes and steroids (45-82% yield).
Abstract: N-(4-Arylazobenzoyl)-1H-benzotriazoles react with hydroxyterpenes, sugars, and steroids in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at room temperature in tetrahydrofuran to afford azo dye labeled terpenes, sugars, and steroids (45-82% yield).
TL;DR: In this article, N-Cbz-(α-amino-β-oxo-α-triphenylphosphoranylidene esters 7a-d induced cyclization to form 2,4-dioxo-3-triphethetrahydropyrrolizine and piperidine.
Abstract: N-Cbz-(α-aminoacyl)benzotriazoles 5a-e reacted with (stabilized-methylene)triphenylphosphoranes 6 and 13 to give the corresponding esters 7a-e (66-91%) or nitriles 14a-e (63-85%). Deprotection of N-Cbz-y-amino-β-oxo-α-triphenylphosphoranylidene esters 7a-d induced cyclization to form 2,4-dioxo-3-triphenylphosphoranylidene pyrrolidines 9a-c (20-98%) and l,3-dioxo-2-triphenylphosphoranylidene tetrahydropyrrolizine 9d (79%). N-Cbz-(δ-amino-β-oxo-α-triphenylphosphoranylidene ester 7e cyclized to form 2,4-dioxo-3-triphenylphosphoranylidene piperidine 9e (60%). Deprotection of N-Cbz-y-amino-β-oxo-a-triphenylphosphoranylidene nitriles 14a-d similarly formed 5-amino-4-triphenylphosphonio-2,4-dihydropyrrol-3-one bromides 15a-c (70-72%) and 3-ammonio-2-triphenylphosphoniotetrahydropyrrolizin-1-one dibromide 15d (66%). N-Methyl pyrrolidine 11 was transformed into 3,3-dibromopyrrolidin-2,4-dione 16 (79%), 3,3-dibromo-5-hydroxypyrrolidin-2,4-dione 17 (88%), 4-azido-3-bromopyrrol-2-one 18 (84%), and 4-benzotriazol-1-ylpyrrol-2-one 19 (92%).