- Design, Synthesis, and Structural Analysis of Cladosporin-Based Inhibitors of Malaria Parasites
-
Here we have described a systematic structure activity relationship (SAR) of a set of compounds inspired from cladosporin, a tool compound that targets parasite (Plasmodium falciparum) lysyl tRNA synthetase (KRS). Four sets of analogues, synthesized based on point changes in the chemical scaffold of cladosporin and other logical modifications and hybridizations, were assessed using high throughput enzymatic and parasitic assays along with in vitro pharmacokinetics. Co-crystallization of the most potent compound in our series (CL-2) with PfKRS revealed its structural basis of enzymatic binding and potency. Further, we report that CL-2 has performed better than cladosporin in terms of metabolic stability. It thus represents a new lead for further optimization toward the development of antimalarial drugs. Collectively, along with a lead compound, the series offers insights on how even the slightest chemical modification might play an important role in enhancing or decreasing the potency of a chemical scaffold.
- Babbar, Palak,Das, Pronay,Manickam, Yogavel,Mankad, Yash,Yadav, Swati,Parvez, Suhel,Sharma, Amit,Reddy, D. Srinivasa
-
p. 1777 - 1794
(2021/05/10)
-
- Efficient flow fischer esterification of carboxylic acids with alcohols using sulfonic acid-functionalized silica as supported catalyst
-
Flow Fischer esterification of carboxylic acids using hydroxy-substituted sulfonic acid-functionalized silica (HOSAS) packed into a stainless steel column reactor was investigated. HO-SAS well catalyzed flow esterification of long chain carboxylic acids with methanol within 3min of residence time at 110°C, and the methyl esters were quantitatively obtained. The flow esterification protocol was applied to the synthesis of a variety of esters (19 examples) and scalable synthesis was also successful.
- Furuta, Akihiro,Fukuyama, Takahide,Ryu, Ilhyong
-
p. 607 - 612
(2017/06/19)
-
- Highly chemoselective esterification reactions and Boc/THP/TBDMS discriminating deprotections under samarium(III) catalysis
-
The usefulness of SmCl3 as an excellent catalyst for chemoselective esterifications and selective removal of acid sensitive protecting groups such as Boc, THP, and TBDMS in the presence of one another is demonstrated through suitable examples.
- Gopinath, Pushparathinam,Nilaya, Surapaneni,Muraleedharan, Kannoth Manheri
-
supporting information; experimental part
p. 1932 - 1935
(2011/06/21)
-
- Total synthesis of silyl-protected early intermediates of polyketide biosynthesis
-
The ketal-or dithioketal-protected isocoumarins 15-18 gave the corresponding 1-naphthols 21-26 in their reactions with the acetoacetate (10) or pentane-2, 4-dione (19) dianions and the acetone monoanion. Subjection of the dithioketal-protected ester 28 to
- Krohn, Karsten,Vidal, Anne,Tran-Thien, Hoan Trang,Floerke, Ulrich,Bechthold, Andreas,Dujardin, Gilles,Green, Ivan
-
scheme or table
p. 3080 - 3092
(2010/08/07)
-
- A domino N-amidoacylation/aldol-type condensation approach to the synthesis of the topo-I inhibitor rosettacin and derivatives
-
(Chemical Equation Presented) The pot, atom, and step-economic synthesis of Rosettacin topo-I poison and its derivatives has been achieved using a novel domino N-amidoacylation/aldol-type condensation, followed by decarboxylation of the ester function. Th
- Pin, Frederic,Comesse, Sebastien,Sanselme, Morgane,Daich, Adam
-
p. 1975 - 1978
(2008/09/18)
-
- The chemistry of homophthalic acid: a new synthetic strategy for construction of substituted isocoumarin and indole skeletons
-
Homophthalic acid was reacted with thionylchloride/DMF and chloroethylformate/NEt3 in the presence and absence of NaN3. In all cases completely different isocoumarin derivatives were obtained. These unusual isocoumarin derivatives were isolated and characterized and their formation mechanisms are discussed. The homophthalic acid monomethyl ester was converted into the corresponding isocyanate. Reaction of the isocyanate with different amines produced the urea derivatives. Base-supported condensation reactions of these products gave first an indolinone derivative, which underwent further intermolecular condensation to give substituted indole derivatives. However, when the condensation reaction was carried out in the presence of acetic anhydride, the intermolecular reactions were suppressed. This methodology opens up a new way of synthesizing of various five-membered ring substituted indole derivatives.
- ?zcan, Sevil,Balci, Metin
-
p. 5531 - 5540
(2008/09/21)
-
- Synthesis and reactivity of 2,3-dihydro-1H-2,3-benzodiazepine-1,4(5H)-dione
-
Based on an orthogonal protective group strategy dealing with N-protected hydrazine, we established for the first time a highly efficient synthetic pathway leading to 2,3-benzodiazepine-1,4-dione. Moreover, the versatile reactivities exhibited by this 2,3
- Bihel, Frederic J.-J.,Hellal, Malik,Bourguignon, Jean-Jacques
-
p. 3791 - 3796
(2008/09/17)
-
- Synthesis and structure activity relationships of novel non-peptidic metallo-aminopeptidase inhibitors
-
Racemic derivatives of 3-amino-2-tetralone were synthesised and evaluated for their ability to inhibit metallo-aminopeptidase activities. New compounds substituted in position 2 by methyl ketone, substituted oximes or hydroxamic acids as well as heterocyclic derivatives were evaluated against representative members of zinc-dependent aminopeptidases: leucine aminopeptidase (E.C. 3.4.11.1), aminopeptidase-N (E.C. 3.4.11.2), Aeromonas proteolytica aminopeptidase (E.C. 3.4.11.10), and the aminopeptidase activity of leukotriene A4 hydrolase (E.C. 3.3.2.6). Several compounds showed Ki values in the low micromolar range against the 'one-zinc' aminopeptidases, while most of them were rather poor inhibitors of the 'two-zinc' enzymes. This interesting selectivity profile may guide the design of new, specific inhibitors of target mammalian aminopeptidases with one active site zinc.
- Albrecht, Sebastien,Defoin, Albert,Salomon, Emmanuel,Tarnus, Celine,Wetterholm, Anders,Haeggstroem, Jasper Z.
-
p. 7241 - 7257
(2007/10/03)
-
- Ozonolysis of enol ethers. Part 10. Ozonization of enol ethers from 1,2- and 1,3-dicarbonyl compounds: Direct quantitative synthesis of phthalonic acid anhydride
-
The results of ozonolyses of enol ethers from 1.2- and 1.3-dicarbonyl compounds presented here strongly indicate that these reactions do not proceed via the established Criegee ozonolysis mechanism for nucleophilic C=C bonds. The quantitative one-step synthesis of phthalonic acid anhydride via ozonolysis of 2-(methoxymethyliden)-1H-inden-1.3(2H)-dione (28a) is described. Furthermore, a revision of the theory of alkene ozonolysis in the presence of tetracyanoethylene (TCNE) is proposed on the basis of a single-electron-transfer (SET) chemistry.
- Schank, Kurt,Beck, Horst,Pistorius, Susanne
-
p. 2025 - 2049
(2007/10/03)
-
- A highly convenient, efficient, and selective process for preparation of esters and amides from carboxylic acids using Fe3+-K-10 montmorillonite clay
-
In the presence of Fe3+-K-10 montmorillonite clay as a catalyst, aliphatic carboxylic acids selectively produced the corresponding esters in the presence of aromatic carboxylic acids by treatment with alcohols. Both the aliphatic and aromatic carboxylic acids formed the amides by reacting with the aliphatic amines, but only the aliphatic carboxylic acids yielded the anilides by treatment with aromatic amines. The catalyst is recoverable and recyclable.
- Srinivas,Das, Biswanath
-
p. 1165 - 1167
(2007/10/03)
-
- Highly efficient esterification of carboxylic acids with alcohols by montmorillonite enwrapped titanium as a heterogeneous acid catalyst
-
Montmorillonite-enwrapped titanium catalyst was found to efficiently promote the esterification of carboxylic acids with alcohols. In comparison to other catalysts reported to date, this heterogeneous catalyst offers a remarkably simple workup procedure, and is reusable without any appreciable loss in its activity and selectivity.
- Kawabata, Tomonori,Mizugaki, Tomoo,Ebitani, Kohki,Kaneda, Kiyotomi
-
p. 9205 - 9208
(2007/10/03)
-
- New approaches to the synthesis of spiro-peroxylactones
-
Ozonolysis of (alkenyldioxy)cyclododecyl hydroperoxides in trifluoroethanol gave a separable mixture of the corresponding a-hydroperoxy- and a-hydroxy-substituted spiro-tetraoxacycloalkanes with ring sizes in the range 7-12. Dehydration of the hydroperoxides or oxidation of the hydroxy-compounds afforded the corresponding peroxylactones. The solid-state structure of 1,2,6,7-tetraoxaspiro[7.11]nonadecan-3-one was determined by X-ray crystallographic analysis.
- McCullough, Kevin J.,Tokuhara, Hidekazu,Masuyama, Araki,Nojima, Masatomo
-
p. 1522 - 1527
(2007/10/03)
-
- A Simple and Efficient Selective Esterification of Aliphatic Carboxylic Acids in the Presence of Aromatic Carboxylic Acids
-
Aliphatic carboxylic acids were esterificated selectively at room temperature in the presence of aromatic carboxylic acids by treatment with alcohols in the presence of silica gel supported NaHSO4 catalyst.
- Das, Biswanath,Venkataiah, B.,Madhusudhan, P.
-
-
- An efficient and regiospecific esterification of dioic acids using PTSA
-
Regiospecific mono alkyl esters of dioic acids have been obtained in excellent yield using PTSA as a catalyst. This method is mild and simpler than the previous methods.
- Rama Devi,Rajaram
-
p. 294 - 296
(2007/10/03)
-
- A simple method for the preparation of monomethyl esters of dicarboxylic acids by selective esterification of the nonconjugated carboxyl group in the presence of an aromatic or conjugated carboxyl group
-
Various dicarboxylic acids have been converted selectively into monomethyl esters in which the nonconjugated carboxyl group is selectively esterified in the presence of an aromatic or conjugated carboxyl group at room temperature (~ 25-27°C) in methanol using a catalytic amount of thionyl chloride.
- Ram, Ram N.,Meher, Nabin Kumar
-
p. 282 - 283
(2007/10/03)
-
- Ring opening of cyclic anhydrides: Synthesis of achiral half-esters using Lewis acids
-
A rapid and high yield preparation of half-esters from cyclic anhydrides using alcohols and Lewis acids is described.
- Sabitha, Gowravaram,Srividya,Yadav
-
p. 4015 - 4018
(2007/10/03)
-
- A selective method for the preparation of aliphatic methyl esters in the presence of aromatic carboxylic acids
-
2,2-Dimethoxypropane, methanol and a catalytic amount of HCl selectively esterify aliphatic carboxylic acids, in the presence of aromatic carboxylic acids, at room temperature and in high yields.
- Rodriguez,Nomen,Spur,Godfroid
-
p. 8563 - 8566
(2007/10/03)
-
- Selective esterification of aliphatic nonconjugated carboxylic acids in the presence of aromatic or conjugated carboxylic acids catalysed by NiCl2.6H2O
-
Unhindered aliphatic nonconjugated carboxylic acids were esterified selectively in the presence of aromatic or conjugated acids on heating in the corresponding alcoholic solutions at reflux for 3-13 hr with 10 mol% of NiCl2.6H2O catalyst.
- Ram, Ram N.,Charles
-
p. 7335 - 7340
(2007/10/03)
-
- Analogues of N(α)-(4-amino-4-deoxypteroyl)-N(δ)-hemiphthaloyl-L- ornithine (PT523) modified in the side chain: Synthesis and biological evaluation
-
Four heretofore undescribed side chain analogues of N(α)-(4-amino-4- deoxypteroyl)-N(δ)-hemiphthaloyl-L-ornithine (PT523, 4) were synthesized via straightforward methods of antifolate chemistry, and their properties were compared with those of PT523 and two related compounds with the aim of defining the contribution of the hemiphthaloyl-L-ornithine moiety to the exceptional in vitro antitumor activity of this novel non-polyglutamatable aminopterin analogue. The IC50 values of N(α)-(4-amino-4-deoxypteroyl)- N(β)-hemiphthaloyl-L-2,3-diaminopropanoic acid (10) and N(α)-(4-amino-4- deoxypteroyl)-N(γ)-hemiphthaloyl-L-2,4-diaminobutanoic acid (9) against A549 human non-small-cell lung carcinoma cells in culture were 23 and 22 nM, whereas those of PT523 and N(α)-(4-amino-4-deoxypteroyl)-N(ε)- hemiphthaloyl-L-lysine (8) were 1.3 and 5.2 nM. A decrease in the in vitro activities of 8 and 9 relative to PT523 was also observed against the panel of cell lines used by the National Cancer Institute to screen new drugs. However the potency of 8 and 9 remained several times greater than that of the historical control methotrexate against many of the cell lines in the screening panel. In an in vivo tumor model, SCC-VII murine squamous cell carcinoma, 9 and methotrexate were well tolerated as 5-day continuous infusions at doses of 0.52 and 0.75 mg/kg/day, whereas the highest tolerated dose of PT523 on this schedule was 0.19 mg/kg/day, in agreement with its lower IC50 in culture. To assess the importance of the hemiphthaloyl group in PT523, N(α)-(4-amino-4-deoxypteroyl)-N(δ)-isophthaloyl-L-ornithine (11), N(α)-(4-amino-4-deoxypteroyl)-N(δ)-terephthaloyl-L-ornithine (12), and N(α)-(4-amino-4-deoxypteroyl)-N(δ)-(4,5-dichlorohemiphthaloyl)-L-ornithine (13) were also synthesized. The IC50 values of 11 and 12 against A549 cells were 45 and 3300 nM, as compared with 1.3 nM for PT523 and 23 nM for methotrexate. In a clonogenic assay against SCC25 human squamous cell carcinoma cells, the IC50 values of 11 and 12 were 2.9 and 72 nM, as compared with 0.3 nM for PT523 and 27 nM for methotrexate. Thus, activity was decreased by moving the aromatic carboxyl group in PT523 to the meta position and was further diminished by moving it to the para position. The IC50 of the halogenated analogue 13 against SCC25 human head and neck squamous carcinoma cells was 18 nM, suggesting lack of tolerance for this 4,5- disubstitution in the phthaloyl moiety. Our results suggest that the combination of a hemiphthaloyl group and three CH2 groups in the side chain are critical determinants of the potent in vitro activity of PT523.
- Rosowsky, Andre,Vaidya, Chitra M.,Bader, Henry,Wright, Joel E.,Teicher, Beverly A.
-
p. 286 - 299
(2007/10/03)
-
- Total synthesis of aklanonic acid and derivatives by Baker-Venkataraman rearrangement
-
Aklanonic acid (1) and the derivatives 2 and 15a-f were prepared by Baker-Venkataraman rearrangement of the corresponding ortho-acetyl anthraquinone esters 13a-e and 14 using lithium hydride in THF. VCH Verlagsgesellschaft mbH, 1996.
- Krohn, Karsten,Roemer, Ernst,Top, Michael
-
p. 271 - 277
(2007/10/03)
-
- THE REGIO- AND STEREOCHEMISTRY OF THE ALKOXIDE-INDUCED RING-OPENING OF METHOXYMETHYLIDENE-SUBSTITUTED HOMOPHTHALIC ANHYDRIDE
-
Ring-opening of methoxymethylidene-substituted homophthalic anhydride (1) by methoxide occurs by two modes.Attack at the 1-position ("benzoate" carbonyl) leads to a stable acid-ester.A combination of unambiguous syntheses and 1H- and 13C-n.m.r. spectrosco
- Hutchings, Michael G.,Chippendale, A. Margaret,Ferguson, Ian
-
p. 3727 - 3734
(2007/10/02)
-
- Use of Phosphorus Pentoxide. Preparation of Half-esters through Selective Esterification
-
Methyl 2-,3-,4-carboxyphenylacetate and methyl 2-,3-,4-carboxyphenoxyacetate have been prepared through selective esterification of the aliphatic carboxylic acid function of the corresponding dicarboxylic acids using a mixture of phosphorus pentoxide (1 part), anhydrous copper sulphate (5 parts) and anhydrous sodium sulphate (5 parts).All the isomeric half-esters have been prepared through partial hydrolysis of the corresponding dimethylesters.
- Banerjee, Amalendu,Adak, Mohini Mohan,Das, Sankar,Banerjee, Santa,Sengupta, Saumitra
-
-
- EFFICIENT DEMETYLATION OF METHYL ESTERS WITH ANHYDROUS TRIFLUOROACETIC ACID
-
Trifluoroacetic acid (TFA) is an effective reagent for the demethylation of methyl esters under anhydrous conditions, affording the parent acids and methyl trifluoroacetate.
- Tabor, Derrick C.,Evans, Slayton A.,Kenan, William Rand
-
p. 855 - 864
(2007/10/02)
-
- PHOTOCHEMICAL RING OPENING REACTIONS OF 3-ALKOXYISOCOUMARIN AND 3-HALO-1-ISOQUINOLONE
-
Irradiation of 3-methoxyisocoumarin (1) in an alcohol afforded two kinds of diester of homophthalic acid (3 and 4) and the mechanism including novel 1,5-sigmatropic methoxy rearrangement from initially formed ketene (5) to the isomeric ketene (6) was proposed.Similar photochemical ring opening reaction of 3-chloro- and -bromo-1-isoquinolones (8 and 9) as well as their novel photoalkoxylation reaction is also described.
- Kaneko, Chikara,Naito, Toshihiko,Miwa, Chiemi
-
p. 2275 - 2278
(2007/10/02)
-