- New amino acid clubbed Schiff bases inhibit carbonic anhydrase II, α-glucosidase, and urease enzymes: in silico and in vitro
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Combating pathological conditions related to hyperactivity of enzymes remains a formidable challenge for health. Small molecules therapy constitutes one of the means to circumvent the medical disorders resulting from enzyme hyperactivity. In this regard, we have synthesized structurally diverse amino acid hybrid Schiff bases (5a–5l and 10a–10k) and evaluated them for carbonic anhydrase II, α-glucosidase, and urease inhibitory potential. These new chemical scaffolds showed variable efficacies against the selected enzymes. The results indicated that compounds 5b (11.8 ± 1.33 μM), 10i (83.3 ± 1.13 μM), and 10f (88.2 ± 2.27 μM) are the most active scaffolds against carbonic anhydrase II, α-glucosidase, and urease, respectively. A structure–activity relationship revealed the most structural features contributing to the overall activities. Molecular docking suggested that these compounds possess excellent binding interactions with the active site residues of the targets by interacting through hydrogen bonding, π–π, and π–cation interactions.
- Al-Harrasi, Ahmed,Al-Yahyaei, Balqees Essa Mohammad,Csuk, Rene,Halim, Sobia Ahsan,Khan, Ajmal,Khan, Majid,Khiat, Mohammed,Muhammed, Niaz,Rafiq, Kashif,Shah, Zarbad,Ur Rehman, Najeeb
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Read Online
- Progress toward the assembly of the bicyclic theonellamide skeleton
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An orthogonally protected τ-histidinoalanine residue was synthesized via regioselective alkylation of optically pure Boc-L-His-OTCE (TCE = trichloroethyl) with a sulfamidate electrophile derived from Fmoc-D-Ser-OBn. The goal was the synthesis of a non-natural theonellamide, invoking readily accessible variants of the other 10 amino acids. Peptide fragments corresponding to the east and west rings of “theonellamide X″ were synthesized in solution. Each ring was formed independently, providing insights into protecting group limitations, side reactions, and the optimal order of events to approach the formation of the bicyclic system. Ultimately, an undecapeptide was prepared, with the eastern ring formed. The twelfth amino acid, an L-α-aminoadipic acid building block, was prepared and preliminary investigations into its attachment to the undecapeptide are reported.
- Batton, Chyree S.,Mukherjee, Jyoti P.,Roy, Joyeeta,Taylor, Carol M.,Wong, Douglas,Yadav, Saroj
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- Asymmetric Mannich Reaction and Construction of Axially Chiral Sulfone-Containing Styrenes in One Pot from α-Amido Sulfones Based on the Waste-Reuse Strategy
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A simultaneous asymmetric Mannich reaction and the construction of axially chiral sulfone-containing styrenes in one pot from α-amido sulfones based on the waste-reuse strategy was demonstrated. A series of chiral β-amino diesters and axially chiral sulfone-containing styrenes with various functional groups were synthesized in good to excellent yields and enantioselectivities under mild conditions. In addition, this protocol has been successfully applied to synthesize the anti-HIV drug Maraviroc and chiral trichloro derivatives.
- Li, Dongmei,Tan, Yu,Peng, Lei,Li, Shan,Zhang, Nan,Liu, Yidong,Yan, Hailong
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supporting information
p. 4959 - 4963
(2018/08/24)
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- NOVEL COMPOUNDS
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The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof, wherein n, X1, X2, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12and R13 are as defined in the specification, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
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Page/Page column 38
(2018/04/12)
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- Disulfonimide-catalyzed asymmetric synthesis of β3-amino esters directly from N-Boc-amino sulfones
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An asymmetric Mannich reaction of silyl ketene acetals with N-Boc-amino sulfones has been developed. A chiral disulfonimide efficiently catalyzes both the in situ generation of the corresponding N-Boc imines and the asymmetric Mannich reaction with excellent yields and enantioselectivities. Kinetic studies confirm a proposed stepwise mechanism.
- Wang, Qinggang,Leutzsch, Markus,Van Gemmeren, Manuel,List, Benjamin
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p. 15334 - 15337
(2013/11/06)
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- Access to 2,6-disubstituted piperidines: Control of the diastereoselectivity, scope, and limitations. applications to the stereoselective synthesis of (-)-solenopsine A and alkaloid (+)-241D
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Scope and limitations in the diastereoselective preparation of 2,6-cis or 2,6-trans disubstituted piperidines are described, through intramolecular reaction of chiral β′-carbamate-α,β-unsaturated ketone. This methodology has been applied to the total synthesis of a few well chosen examples, such as (-)-solenopsine A and alkaloid (+)-241D.
- Abrunhosa-Thomas, Isabelle,Plas, Aurelie,Vogrig, Alexandre,Kandepedu, Nishanth,Chalard, Pierre,Troin, Yves
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p. 2511 - 2526
(2013/04/24)
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- Efficient synthesis of β'-amino-α, β-unsaturated ketones
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A general and simple procedure to access chiral β'-amino-α, β-enones, in seven steps, from an α,β unsaturated ester has been described. The use of a Horner-Wadsworth-Emmons reaction as a key step for generating the β'-amino-α,β-enones, permits access to a range of substrates under mild conditions and in moderate to high yield.
- Abrunhosa-Thomas, Isabelle,Plas, Aurelie,Kandepedu, Nishanth,Chalard, Pierre,Troin, Yves
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p. 486 - 495
(2013/04/23)
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- PREPARATION AND UTILITY OF CCR5 INHIBITORS
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Disclosed herein are substituted 8-azabicyclo[3.2.1]octane-based anti-infective agents of Formula I, processes of preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 39
(2008/12/06)
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- Discovery of a novel CCR5 antagonist lead compound through fragment assembly
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CCR5, as the major co-receptor for HIV-1 entry, is an attractive novel target for the pharmaceutical industry in the HIV-1 therapeutic area. In this study, based on the structures of maraviroc and 1,4-bis(4-(7-chloroquinolin-4- yl)piperazin-1-yl)butane-1,4-dione (1), which was identified using structure-based virtual screening in conjunction with a calcium mobilization assay, a series of novel small molecule CCR5 antagonists have been designed and synthesized through fragment assembly. Preliminary SARs were obtained, which are in good agreement with the molecular binding model and should prove helpful for future antagonist design. The novel scaffold presented here might also be useful in the development of maraviroc-derived second generation CCR5 antagonists.
- Liu, Yanqing,Zhou, Enkun,Yu, Kunqian,Zhu, Jin,Zhang, Yu,Xie, Xin,Li, Jian,Jiang, Hualiang
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experimental part
p. 2426 - 2441
(2009/04/11)
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- Enantioselective synthesis of (S)-dapoxetine
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An efficient enantioselective synthesis leading directly to (+)-(S)-dapoxetine has been described for the first time using a Sharpless asymmetric dihydroxylation, Barton-McCombie deoxygention, and Mitsunobu reaction as the key steps.
- Siddiqui, Shafi A.,Srinivasan, Kumar V.
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p. 2099 - 2103
(2008/02/11)
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- Organocatalytic asymmetric mannich reactions with JV-Boc and JV-Cbz protected α-amido sulfones (Boc: Tert-butoxycarbonyl, Cbz: Benzyloxycarbonyl)
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Different malonates and βketoesters can react with N-tert-butoxycarbonyl- (N-Boc) and N-benzyloxycarbonyl- (N-Cbz) protected α-amido sulfones in an organocatalytic asymmetric Mannich-type reaction. The reaction makes use of a simple and easily obtained ph
- Marianacci, Olindo,Micheletti, Gabriele,Bernardi, Luca,Fini, Francesco,Fochi, Mariafrancesca,Pettersen, Daniel,Sgarzani, Valentina,Ricci, Alfredo
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p. 8338 - 8351
(2008/04/01)
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- PROCESS TO CHIRAL BETA AMINO ACID DERIVATIVES BY ASYMMETRIC HYDROGENATION
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The present invention relates to a process for the efficient preparation of enantiomerically enriched beta amino acid derivatives which are useful in the asymmetric synthesis of biologically active molecules. The process comprises an enantioselective hydrogenation of a prochiral beta amino acrylic acid derivative substrate in the presence of a transition metal precursor complexed with a chiral ferrocenyl diphosphine ligand with in situ protection of the primary amine product. The invention also relates to a novel process for the preparation of chiral beta-amino acid amides as inhibitors of the dipeptidyl peptidase-IV of structural formula III and the useful intermediates obtained therein. The products resulting from the instant process are inhibitors of dipeptidyl peptidase-IV and thereby useful for the treatment of Type 2 diabetes.
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Page/Page column 29; 30
(2010/11/08)
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- Direct enantio- and diastereoselective Mannich reactions of malonate and β-keto esters with N-Boc and N-Cbz aldimines catalysed by a bifunctional cinchonine derivative
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A highly enantioselective Mannich reaction between malonate esters and N-Boc and N-Cbz aldimines, catalysed by a bifunctional cinchonine derivative, has been developed; extension of this methodology to encompass the use of 2-substituted-1,3-dicarbonyl nuc
- Tillman, A. Louise,Ye, Jinxing,Dixon, Darren J.
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p. 1191 - 1193
(2008/02/03)
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- Detection and elimination of product inhibition from the asymmetric catalytic hydrogenation of enamines
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(Chemical Equation Presented) The catalytic asymmetric hydrogenation of enamine amides and esters with catalyst Rh-1a, prepared from ferrocenyl based ligand 1a or 1b and [(COD)RhCl]2, has been shown through kinetic studies to suffer from product inhibition. Enamine ester substrates have also been shown to be incompatible with the amine products of the reaction in methanol. In situ protection of the amine products with di-tert-butyl dicarbonate eliminates functional group incompatibility of ester substrates and eliminates product inhibition in the reaction.
- Hansen, Karl B.,Rosner, Thorsten,Kubryk, Michele,Dormer, Peter G.,Armstrong III, Joseph D.
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p. 4935 - 4938
(2007/10/03)
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- Lewis acid-Lewis acid heterobimetallic cooperative catalysis: Mechanistic studies and application in enantioselective Aza-Michael reaction
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The full details of a catalytic asymmetric aza-Michael reaction of methoxylamine promoted by rare earth-alkali metal heterobimetallic complexes are described, demonstrating the effectiveness of Lewis acid-Lewis acid cooperative catalysis. First, enones we
- Yamagiwa, Noriyuki,Qin, Hongbo,Matsunaga, Shigeki,Shibasaki, Masakatsu
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p. 13419 - 13427
(2007/10/03)
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- Initial synthesis of UK-427,857 (Maraviroc)
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The initial synthesis of UK-427,857 (Maraviroc) is described including the preparation of 4,4-difluorocyclohexanoic acid and amide coupling utilizing a polymer supported reagent.
- Price, David A.,Gayton, Simon,Selby, Matthew D.,Ahman, Jens,Haycock-Lewandowski, Sarah,Stammen, Blanda L.,Warren, Andrew
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p. 5005 - 5007
(2007/10/03)
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- N-(3-(4-substituted-1-piperidinyl)-1-phenylpropyl) substituted sulfonamides as NK-3 receptor antagonists
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The present invention provides a method of treatment of a subject suffering from a disease, such as schizophrenia, for which the administration of an NK-3 antagonist is indicated which comprises administering to that subject a therapeutically effective amount of a compound of formula I: wherein, generally, Q is R1 is benzyl, phenyl, thiophene or imidazolyl optionally substituted with C1-4alkyl or halogen, such as methyl, fluorine or bromine; R2 is hydrogen or C1-4alkyl such as methyl; R3 is phenyl; R4 is hydrogen; R5 is hydrogen or C1-6alkylcarbonyl such as methylcarbonyl; X is —SO2— or —C(O)N(R2)SO2— where R2 is preferably hydrogen; Y is a bond, CH2 or Z1 where Z1 is —N(Rf)— in which Rf is C1-6alkylcarbonyl such as ethylcarbonyl; and R6 is phenyl, pyrazolyl, pyridyl, pyrimidinyl or benzimidazolonyl optionally substituted with one or two groups chosen from C1-6alkyl and benzyl, such as methyl, ethyl and benzyl; or a pharmaceutically acceptable salt thereof.
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Page/Page column 37
(2010/11/30)
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- Modulators of CCR5 chemokine receptor activity
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Compounds of Formula I: (wherein R1, R2, R3, R4, Q, and X are defined herein) are described. The compounds are modulators of CCR5 chemokine receptor activity. The compounds are useful, for example, in the prevention or treatment of infection by HIV and the treatment of AIDS, as compounds or pharmaceutically acceptable salts, or as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.
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- Tropane derivatives useful in therapy
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The present invention provides compounds of the formula: wherein R1 is C3-6 cycloalkyl optionally substituted by one or more fluorine atoms, or C1-6 alkyl optionally substituted by one or more fluorine atoms, or C3-6 cycloalkylmethyl optionally ring-substituted by one or more fluorine atoms; and R2 is phenyl optionally substituted by one or more fluorine atoms, to pharmaceutically acceptable salts and solvates thereof, and to processes for the preparation of, intermediates used in the preparation of, compositions containing and the uses of, such compounds.
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- A convenient synthesis of chiral β3-amino acids
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A novel method for the synthesis of chiral β3-amino acids is developed where the acid functionality was built by oxidative cleavage of an α-allylic group that was introduced by Evans' asymmetric alkylation of an appropriate acid substrate and the amino part came from the amide of the original carboxyl group following a modified Hofmann rearrangement reaction.
- Chakraborty, Tushar K.,Ghosh, Animesh
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p. 2039 - 2040
(2007/10/03)
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- An allyltitanium derived from acrolein 1,2-dicyclohexylethylene acetal and (η2-propene)Ti(o-i-Pr)2 as a chiral propionaldehyde homoenolate equivalent that reacts with imines with excellent stereoselectivity. An efficient and practical access to optically active γ-amino carbonyl compounds
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A chiral allyltitanium compound 2, prepared in situ by the reaction of optically active acrolein 1,2-dicyclohexylethylene acetal (3) with (η2-propene)Ti(O-i-Pr)2 (1), reacts with a variety of acyclic and cyclic imines 4 in a regiospecific way to afford α-addition products 5 as a mixture of the E- and Z-isomers in good combined yield, where the former is predominant in a ratio of 92: 8 to >95:5. The mixture of (E)- and (Z)-5 and pure (E)-5 which could be isolated in several cases were respectively converted to the corresponding β-amino ester 6 to confirm the absolute configuration and enantiomeric purity. The ee of the newly formed asymmetric center of 5 is more than 78% for the mixture of (E)- and (Z)-5 and more than 96% for pure (E)-5. By taking advantage of the versatility of the vinyl ether moiety in 5, optically active γ-amino aldehydes 8, γ-amino aldehyde acetals 7 and 10, γ-amino acids 9, β-amino esters 6, and pyrrolidinoisoquinolines 12 were readily prepared. In the reaction of 2 with optically active α-silyloxyimine 4n, remarkable double stereodifferentiation was observed; thus, the reaction of 2 derived from (S,S)- or (R,R)-3 provided syn- and anti-5n in a ratio of 55:45 or 0:100, respectively. Meanwhile, the stereochemistry of the product in the reaction of 2 with β-silyloxyimine 4o was controlled mainly by 2. Thus, the reaction of β-silyloxyimine 14 with 2 derived from 1 and (R,R)-3 afforded γ-silyloxyimine 15 with 92% diastereoselectivity, from which 4-amino6-hydroxypentadecanal dimethyl acetal (13), a key intermediate for the synthesis of batzelladine D, was synthesized.
- Okamoto,Teng,Fujii,Takayama,Sato
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p. 3462 - 3471
(2007/10/03)
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- Fibrinogen receptor antagonists
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Fibrinogen receptor antagonists having the structure, for example, of STR1 for example STR2
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- A Concise Enantioselective Synthesis of Allylamines and N-Boc-β-Amino Acids
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A new and efficient enantioselective synthesis of allylamines and N-Boc-β-amino acids has been developed.Starting from enantiomerically enriched N-diphenylmethyl-3-amino-1,2-diols, allylamines are easily obtained by a Corey-Hopkins deoxygenative protocol.After a change in the nitrogen protecting group, the resulting N-Boc allylamines are converted into β-amino acids by hydroboration with 9-BBN followed by oxidation with PDC in DMF.
- Alcon, Montserrat,Canas, Marc,Poch, Marta,Moyano, Albert,Pericas, Miquel A.,Riera, Antoni
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p. 1589 - 1592
(2007/10/02)
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