- Design, Synthesis, and Biological Evaluation of Novel Pyrimido[4,5-b]indole Derivatives against Gram-Negative Multidrug-Resistant Pathogens
-
Due to the poor permeability across Gram-negative bacterial membranes and the troublesome bacterial efflux mechanism, only a few GyrB/ParE inhibitors with potent activity against Gram-negative pathogens have been reported. Among them, pyrimido[4,5-b]indol
- Kong, Qidi,Pan, Wei,Xu, Heng,Xue, Yaru,Guo, Bin,Meng, Xin,Luo, Cheng,Wang, Ting,Zhang, Shuhua,Yang, Yushe
-
supporting information
p. 8644 - 8665
(2021/06/28)
-
- Integration of Enhanced Sampling Methods with Saturation Transfer Difference Experiments to Identify Protein Druggable Pockets
-
Saturation transfer difference (STD) is an NMR technique conventionally applied in drug discovery to identify ligand moieties relevant for binding to protein cavities. This is important to direct medicinal chemistry efforts in small-molecule optimization processes. However, STD does not provide any structural details about the ligand-target complex under investigation. Herein, we report the application of a new integrated approach, which combines enhanced sampling methods with STD experiments, for the characterization of ligand-target complexes that are instrumental for drug design purposes. As an example, we have studied the interaction between StOASS-A, a potential antibacterial target, and an inhibitor previously reported. This approach allowed us to consider the ligand-target complex from a dynamic point of view, revealing the presence of an accessory subpocket which can be exploited to design novel StOASS-A inhibitors. As a proof of concept, a small library of derivatives was designed and evaluated in vitro, displaying the expected activity.
- Magalh?es, Joana,Annunziato, Giannamaria,Franko, Nina,Pieroni, Marco,Campanini, Barbara,Bruno, Agostino,Costantino, Gabriele
-
p. 710 - 723
(2018/03/30)
-
- Rational Design, Synthesis, and Preliminary Structure-Activity Relationships of α-Substituted-2-Phenylcyclopropane Carboxylic Acids as Inhibitors of Salmonella typhimurium O-Acetylserine Sulfhydrylase
-
Cysteine is a building block for several biomolecules that are crucial for living organisms. The last step of cysteine biosynthesis is catalyzed by O-acetylserine sulfydrylase (OASS), a highly conserved pyridoxal 5′-phosphate (PLP)-dependent enzyme, present in different isoforms in bacteria, plants, and nematodes, but absent in mammals. Beside the biosynthesis of cysteine, OASS exerts a series of moonlighting activities in bacteria, such as transcriptional regulation, contact-dependent growth inhibition, swarming motility, and induction of antibiotic resistance. Therefore, the discovery of molecules capable of inhibiting OASS would be a valuable tool to unravel how this protein affects the physiology of unicellular organisms. As a continuation of our efforts toward the synthesis of OASS inhibitors, in this work we have used a combination of computational and spectroscopic approaches to rationally design, synthesize, and test a series of substituted 2-phenylcyclopropane carboxylic acids that bind to the two S. typhymurium OASS isoforms at nanomolar concentrations.
- Pieroni, Marco,Annunziato, Giannamaria,Beato, Claudia,Wouters, Randy,Benoni, Roberto,Campanini, Barbara,Pertinhez, Thelma A.,Bettati, Stefano,Mozzarelli, Andrea,Costantino, Gabriele
-
p. 2567 - 2578
(2016/04/10)
-
- Palladium-Catalyzed Long-Range Deconjugative Isomerization of Highly Substituted α,β-Unsaturated Carbonyl Compounds
-
The long-range deconjugative isomerization of a broad range of α,β-unsaturated amides, esters, and ketones by an in situ generated palladium hydride catalyst is described. This redox-economical process is triggered by a hydrometalation event and is thermodynamically driven by the refunctionalization of a primary or a secondary alcohol into an aldehyde or a ketone. Di-, tri-, and tetrasubstituted carbon-carbon double bonds react with similar efficiency; the system is tolerant toward a variety of functional groups, and olefin migration can be sustained over 30 carbon atoms. The refunctionalized products are usually isolated in good to excellent yield. Mechanistic investigations are in support of a chain-walking process consisting of repeated migratory insertions and β-H eliminations. The bidirectionality of the isomerization reaction was established by isotopic labeling experiments using a substrate with a double bond isolated from both terminal functions. The palladium hydride was also found to be directly involved in the product-forming tautomerization step. The ambiphilic character of the in situ generated [Pd-H] was demonstrated using isomeric trisubstituted α,β-unsaturated esters. Finally, the high levels of enantioselectivity obtained in the isomerization of a small set of α-substituted α,β-unsaturated ketones augur well for the successful development of an enantioselective version of this unconventional isomerization.
- Lin, Luqing,Romano, Ciro,Mazet, Clément
-
supporting information
p. 10344 - 10350
(2016/08/31)
-
- Discovery of New Potential Anti-Infective Compounds Based on Carbonic Anhydrase Inhibitors by Rational Target-Focused Repurposing Approaches
-
In academia, compound recycling represents an alternative drug discovery strategy to identify new pharmaceutical targets from a library of chemical compounds available in house. Herein we report the application of a rational target-based drug-repurposing approach to find diverse applications for our in-house collection of compounds. The carbonic anhydrase (CA, EC 4.2.1.1) metalloenzyme superfamily was identified as a potential target of our compounds. The combination of a thoroughly validated docking screening protocol, together with in vitro assays against various CA families and isoforms, allowed us to identify two unprecedented chemotypes as CA inhibitors. The identified compounds have the capacity to preferentially bind pathogenic (bacterial/protozoan) CAs over human isoforms and represent excellent hits for further optimization in hit-to-lead campaigns.
- Annunziato, Giannamaria,Angeli, Andrea,D'Alba, Francesca,Bruno, Agostino,Pieroni, Marco,Vullo, Daniela,De Luca, Viviana,Capasso, Clemente,Supuran, Claudiu T.,Costantino, Gabriele
-
p. 1904 - 1914
(2016/10/12)
-
- Further insights into the SAR of α-substituted cyclopropylamine derivatives as inhibitors of histone demethylase KDM1A
-
Epigenetics alterations including histone methylation and acetylation, and DNA methylation, are thought to play important roles in the onset and progression of cancer in numerous tumour cell lines. Lysinespecific demethylase 1 (LSD1 or KDM1A) is highly ex
- Pieroni, Marco,Annunziato, Giannamaria,Azzali, Elisa,Dessanti, Paola,Mercurio, Ciro,Meroni, Giuseppe,Trifiró, Paolo,Vianello, Paola,Villa, Manuela,Beato, Claudia,Varasi, Mario,Costantino, Gabriele
-
p. 377 - 386
(2015/03/05)
-
- Dialkylation of diethyl ethoxycarbonylmethylphosphonate under microwave and solventless conditions
-
To further broaden the methods for the heterogeneous phase alkylation of CH acidic compounds, the dialkylation of diethyl ethoxycarbonylmethylphosphonate was studied in the presence of Cs2CO3 under microwave and solvent-free conditio
- Gruen, Alajos,Blastik, Zsofia,Drahos, Laszlo,Keglevich, Gyoergy
-
p. 107 - 113
(2014/04/03)
-
- Diastereospecific nazarov cyclization of fully substituted dienones: Generation of vicinal all-carbon-atom quaternary stereocenters
-
No vacancy: Fully substituted dienones that are highly polarized by a vinylogous carbonate group were found to undergo a remarkably rapid and diastereospecific Nazarov cyclization that led to cyclopentenones with vicinal all-carbon-atom quaternary centers (see example; SEM=2-(trimethylsilyl) ethoxymethyl, Tf=trifluoromethanesulfonyl). Copyright
- Jolit, Anais,Vazquez-Rodriguez, Saleta,Yap, Glenn P. A.,Tius, Marcus A.
-
supporting information
p. 11102 - 11105
(2013/10/22)
-
- Microwave-assisted alkylation of diethyl ethoxycarbonylmethylphosphonate under solventless conditions
-
The reaction of diethyl ethoxycarbonylmethylphosphonate with a series of alkyl halides, under microwave (MW) and solventless conditions at 120°C, in the presence of Cs2CO3 and in the absence of a phase transfer catalyst afforded the corresponding monoalkylated products in yields of >70%. The thermal variant carried out in boiling acetonitrile was slow and led to incomplete conversions. In the MW method, the phase transfer catalyst is substituted by MW irradiation and there is no need for a solvent.
- Gruen, Alajos,Blastik, Zsofia,Drahos, Laszlo,Keglevich, Gyoergy
-
experimental part
p. 241 - 246
(2012/07/28)
-
- Investigation on lewis acid mediated diels-alder reactions of 2-phosphono-2-alkenoates. Application to total synthesis of (±)-α- alasken-8-one via reductive alkylation of resulting adduct
-
(Chemical Equation Presented) The Lewis acid mediated Diels-Alder reactions of three 2-phosphono-2-alkenoates including triethyl 2-phosphonoacrylate (1), triethyl 2-phosphonobut-2-enoate (2), and ethyl 2-(diethoxyphosphono)-3- methylbut-2-enoate (3) have been investigated. Of several Lewis acids tested, tin(IV) chloride was shown to be the most effective at enhancing the regio- and stereoselectivity of the reactions of 1 with the electron-rich dienes to result in the formation of the single regio- and/or stereoisomers in good yields. Bearing the β methyl group(s), 2 displayedmuch less reactivity than 1 while 3 was completely unreactive under the study's conditions. Throughout the investigation, we found that the cycloadditions of 2, especially of the Z-isomer, could be efficiently induced by using zinc chloride at elevated temperatures. Furthermore, a lithium naphthalenide (LN)-induced reductive alkylation process was applied to the resulting Diels-Alder adducts 4 to allow the phosphono group at the quaternary carbon centers to be replaced by various alkyl groups to afford the alkyl-substituted esters 12, therefore practically turning 1 and 2 into the useful synthetic equivalents of the corresponding 2-alkyl 2-alkenoates that usually display poor Diels-Alder reactivity. Application of this combined operation has facilitated the total synthesis of the sesquiterpene natural product α-alasken-8-one (8) in racemic form.
- Liao, Chuan-Cheng,Zhu, Jia-Liang
-
body text
p. 7873 - 7884
(2010/01/16)
-
- Absolute configuration and synthesis of β- and δ-lactones present in the pheromone system of the giant white butterfly Idea leuconoe
-
Males of the giant white butterfly Idea leuconoe release a complex mixture of compounds during courtship. Besides alkaloids, aromatics, terpenoids and hydrocarbons, several lactones have been identified in the pheromone bouquet. Two simple stereoselective methods to create the lactones in good enantiomeric excesses have been developed. The generation of the stereocenters of the β-lactones la and lb is based on a controlled C-C coupling by a Horner-Wadsworth-Emmons approach, followed by asymmetric dihydroxylation, whereas the synthesis of the δ-lactone 3b uses an enantioselective hydrogenation of a dioxoalkanoate precursor. The absolute configurations of the natural lactones 1a, 1b and 3b were determined by gas chromatography on a chiral stationary phase. Both 1a and 1b are of (S,S) configuration, suggesting their biosynthetic origin from (-)-viridifloric acid (7a) or (-)norviridifloric acid (7b), respectively. In contrast, natural 3b is a mixture of all enantiomers, in which the (5S,7S) enantiomer dominates. Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002.
- Stritzke, Katja,Schulz, Stefan,Nishida, Ritsuo
-
p. 3884 - 3892
(2007/10/03)
-
- Synthesis and SAR of 1-alkyl-2-phenylethylamine derivatives designed from N,N-dipropyl-4-methoxy-3-(2-phenylethoxy)phenylethylamine to discover σ1 ligands
-
The synthesis and structure-activity relationships (SAR) of 1-alkyl-2- phenylethylamine derivatives 5-8 designed from N,N-dipropyl-2-[4-methoxy-3- (2-phenylethoxy)phenyl]ethylamine hydrochloride (1, NE-100) are presented. The SAR between compound 1 and 1-alkyl-2-phenylethylamine derivatives suggested that the alkyl group on the 1-position carbon of 2-[4-methoxy-3-(2- phenylethyl)phenyl]ethylamine derivatives played the role of one of the propyl groups on the aminic nitrogen of compound 1. (-)-N-Propyl-1-butyl-2- [4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine hydrochloride ((-)-6d, NE-537) and (-)-N-propyl-1-(3-methybutyl)-2-[4-methoxy-3-(2- phenylethoxy)phenyl]ethylamine hydrochloride ((-)-6i, NE-535), typical compounds in this series, have potent and selective σ1 affinity.
- Nakazato, Atsuro,Kumagai, Toshihito,Ohta, Kohmei,Chaki, Shigeyuki,Okuyama, Shigeru,Tomisawa, Kazuyuki
-
p. 3965 - 3970
(2007/10/03)
-
- N-ACYLAMINO ACID DERIVATIVES AND THEIR PHARMACEUTICAL COMPOSITIONS
-
An N-acylamino acid derivative of the formula: STR1 wherein the substituents are herein defined or a salt thereof, which is useful as hypotensive drugs.
- -
-
-
- Reaction of Diethyl Phosphorochloridite with Enolates: A General Method for Synthesis of β-Keto Phosphonates and α-Phosphono Esters through C-P Bond Formation
-
The reaction of ketone enolates with diethyl phosphorochloridite, followed by air oxidation of the intermediate reaction products, has proven to be a general and convenient method for preparation of β-keto phosphonates.Fourteen β-keto phosphonates have been prepared by this method, in an average yield greater than 60percent.This procedure also appears to be applicable to preparation of both α-phosphono aldehydes and α-phosphono esters.Although special precautions may be necessary to avoid aldol condensation during formation of aldehyde enolates, in two cases it was shown that the resulting enolates react readily with diethyl chlorophosphite.Finally, a set of five ethyl esters was converted to α-phosphono esters by this method.Yields of the α-phosphono esters are influenced by steric hindrance at the enolate carbon, but the average yield for this series was ca. 70percent.Because this synthetic method relies upon an electrophilic phosphorus reagent for formation of the C-P bond, it is complementary to the traditional Arbuzov synthesis.On the basis of the 21 examples presented here, it appears to be more widely applicable.
- Lee, Koo,Wiemer, David F.
-
p. 5556 - 5560
(2007/10/02)
-
- Synthesis of α-Phosphono Lactones and Esters through a Vinyl Phosphate-Phosphonate Rearrangement
-
Upon treatment with base, the diethyl vinyl phosphate derivatives of five-, six-, and seven-membered-ring lactones undergo rearrangement to α-phosphono lactones in very good yields.Because the vinyl phosphates can be prepared in situ, these α-phosphono lactones can be obtained from the parent lactones in a one-flask protocol, making this methodology a convenient alternative to the traditional Arbuzov synthesis.An analogous reaction sequence can be used to prepare some α-phosphono esters, but yields are generally lower and the rearrangement becomes minimal with esters hindered at the β-position.
- Jackson, John A.,Hammond, Gerald B.,Wiemer, David F.
-
p. 4750 - 4754
(2007/10/02)
-
- α-LITHIOALKYLPHOSPHONATES AS FUNCTIONAL GROUP CARRIERS. AN IN SITU ACRYLIC ESTER SYNTHESIS
-
Condensation of α-lithioalkylphosphonates with diethylcarbonate in the presence of LDA generates carbethoxyalkylphosphonate anions which upon treatment at room temperature with aldehydes constitutes an in situ acrylic ester synthesis.
- Tay, M. K.,About-Jaudet, E.,Collignon, N.,Teulade, M. P.,Savignac, Ph.
-
p. 1349 - 1362
(2007/10/02)
-
- 5-Substituted amino-4-hydroxy-pentenoic acid derivatives and their use
-
A 5-substituted amino-4-hydroxy-pentenoic acid or its salt represented by the formula: wherein each of R1 and R2 which may be the same or different is a hydrogen atom, a lower alkyl group, an aralkyl group, a lower alkoxycarbonyl group, an aryloxycarbonyl group, an aralkyloxycarbonyl group or a lower alkanoyl group which may be substituted by from one to three substituents selected from the group consisting of an amino group, a hydroxyl group, a carboxyl group, an aryloxy group, an aralkyloxycarbonylamino group, a lower alkoxycarbonylamino group and a group (wherein each of X1 and X2 which may be the same or different is a hydrogen atom, a lower alkyl group, an aryl group or an aralkyl group, or X1 and X2 form together with the adjacent nitrogen atom a 5- or 6-membered heterocyclic group which may further contain a hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom) and which may further contain a double bond in its carbon chain, each of R3, R4 and R6 which may be the same or different is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aryl group, an aralkyl group or a residue of an acidic, neutral or basic amino acid, R5 is a hydrogen atom or a lower alkyl group, R7 is a hydrogen atom, a lower alkyl, cycloalkyl, cycloalkylalkyl or aralkyl group which may be substituted by one or two hydroxyl groups or a residue of an acidic, neutral or basic amino acid, R8 is a hydroxyl group, a -OY group (wherein Y is a lower alkyl group, an aryl group, an aralkyl group, a lower alkoxyalkyl group, a lower alkanoyloxyalkyl group, a lower alkoxycarbonyloxyalkyl group, or a 1-phthalidyl group) or a group (wherein each of Y1 and Y2 which may be the same or different is a hydrogen atom, a lower alkyl group, an aryl group, an aralkyl group or a cycloalkyl group, or Y1 and Y2 form together with the adjacent nitrogen atom a 5- or 6-membered heterocyclic group which may further contain a hetero atom selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom), and each of n and m which may be the same or different is 0 or 1.
- -
-
-
- Alpha-alkyl polyolefinic carboxylic acids and derivatives thereof useful in the treatment of psoriasis and allergic responses
-
Polyolefinic compounds represented by the general formula STR1 in which R and R1 are each hydrogen or an alkyl group of from 1 to 5 carbon atoms; R2 is an alkyl group of from 1 to 5 carbon atoms; R3 is hydroxyl, alkoxy of
- -
-
-
- Alpha-alkyl polyolefinic carboxylic acids and derivatives thereof useful in the treatment of psoriasis and allergic responses
-
Polyolefinic compounds represented by the general formula STR1 in which R and R1 are each hydrogen or an alkyl group of from 1 to 5 carbon atoms; R2 is an alkyl group of from 1 to 5 carbon atoms; R3 is hydroxyl, alkoxy of
- -
-
-
- Polyene compounds useful in the treatment of psoriasis and allergic responses
-
Polyene compounds represented by the general formulae STR1 in which: R and R1 are each hydrogen or an alkyl group of from 1 to 5 carbon atoms; R2 is an alkyl group of from 1 to 5 carbon atoms; R3 is hydroxyl, alkoxy of from 1 to 5 carbon atoms, NH2, NHR2 or NR2 R2 and Z is a cycloalkyl, cycloalkenyl or cycloalkdienyl group substituted with from 0 to 5 alkyl groups, a keto group or a hydroxyl group or a phenyl group substituted with from 0 to 4 hydroxy, alkoxy, alkyl, aryloxy, aralkyloxy or trifluoromethyl groups or halogen atoms or combinations thereof and the pharmaceutically-acceptable salts thereof. The foregoing compounds have been found to be effective in the treatment of psoriasis, inflammatory conditions and allergic responses.
- -
-
-