99113-35-6Relevant academic research and scientific papers
Peptidomimetic plasmepsin inhibitors with potent anti-malarial activity and selectivity against cathepsin D
Zogota, Rimants,Kinena, Linda,Withers-Martinez, Chrislaine,Blackman, Michael J.,Bobrovs, Raitis,Pantelejevs, Teodors,Kanepe-Lapsa, Iveta,Ozola, Vita,Jaudzems, Kristaps,Suna, Edgars,Jirgensons, Aigars
, p. 344 - 352 (2018/12/11)
Following up the open initiative of anti-malarial drug discovery, a GlaxoSmithKline (GSK) phenotypic screening hit was developed to generate hydroxyethylamine based plasmepsin (Plm) inhibitors exhibiting growth inhibition of the malaria parasite Plasmodium falciparum at nanomolar concentrations. Lead optimization studies were performed with the aim of improving Plm inhibition selectivity versus the related human aspartic protease cathepsin D (Cat D). Optimization studies were performed using Plm IV as a readily accessible model protein, the inhibition of which correlates with anti-malarial activity. Guided by sequence alignment of Plms and Cat D, selectivity-inducing structural motifs were modified in the S3 and S4 sub-pocket occupying substituents of the hydroxyethylamine inhibitors. This resulted in potent anti-malarials with an up to 50-fold Plm IV/Cat D selectivity factor. More detailed investigation of the mechanism of action of the selected compounds revealed that they inhibit maturation of the P. falciparum subtilisin-like protease SUB1, and also inhibit parasite egress from erythrocytes. Our results indicate that the anti-malarial activity of the compounds is linked to inhibition of the SUB1 maturase plasmepsin subtype Plm X.
Plasmepsin inhibitory activity and structure-guided optimization of a potent hydroxyethylamine-based antimalarial hit
Jaudzems, Kristaps,Tars, Kaspars,Maurops, Gundars,Ivdra, Natalija,Otikovs, Martins,Leitans, Janis,Kanepe-Lapsa, Iveta,Domraceva, Ilona,Mutule, Ilze,Trapencieris, Peteris,Blackman, Michael J.,Jirgensons, Aigars
supporting information, p. 373 - 377 (2014/05/06)
Antimalarial hit 1SR (TCMDC-134674) identified in a GlaxoSmithKline cell based screening campaign was evaluated for inhibitory activity against the digestive vacuole plasmepsins (Plm I, II, and IV). It was found to be a potent Plm IV inhibitor with no selectivity over Cathepsin D. A cocrystal structure of 1SR bound to Plm II was solved, providing structural insight for the design of more potent and selective analogues. Structure-guided optimization led to the identification of structurally simplified analogues 17 and 18 as low nanomolar inhibitors of both, plasmepsin Plm IV activity and P. falciparum growth in erythrocytes.
From L-ascorbic acid to protease inhibitors: Practical synthesis of key chiral epoxide intermediates for aspartyl proteases
Chang, Sun Ki,So, Soon Mog,Lee, Sang Min,Kim, Min Kyu,Seol, Kyoung Mee,Kim, Sung Min,Kang, Jae Sung,Choo, Dong Joon,Lee, Jae Yeol,Kim, B. Moon
experimental part, p. 2213 - 2218 (2012/09/21)
Efficient synthetic routes were developed to prepare a sizable amount (4-15 grams) of the chiral epoxides 4-6 as versatile intermediates for the synthesis of aspartyl protease inhibitors of therapeutic interest such as HIV protease and β-secretase. Oxidative cleavage of the C(2)-C(3) double bond of L-ascorbic acid followed by functional group manipulation led to the preparation of the epoxide 10, which was opened with an azide to yield a common aziridine intermediate 12. Through opening of the aziridine ring of 12 with either a carbon or a sulfur nucleophile, chiral epoxide precursors 4-6 could be prepared for various HIV protease inhibitors. Except for the final low melting epoxides 5 and 6, all intermediates were obtained as crystalline solids, thus the synthetic pathway can be easily applied to a large-scale synthesis of the chiral epoxides.
An efficient synthesis of N-protected threo (2R,3S)-3-amino-1,2-epoxy phenylbutane
Suzuki, Takayuki,Honda, Yutaka,Izawa, Kunisuke
, p. 5811 - 5814 (2007/10/03)
A precise and versatile method was developed for the synthesis of threo amino epoxide derivatives, which are useful intermediates for protease inhibitors. It involves the diastereoselective reduction of the carbonyl group of γ-N,N-dibenzyl amino α-hydroxy β-keto sulfide prepared from an amino acid, and its subsequent stereospecific conversion to an amino epoxide via acetoxy halogenation in high yield.
Application of the lewis acid-lewis base bifunctional asymmetric catalysts to pharmaceutical syntheses: Stereoselective chiral building block syntheses of human immunodeficiency virus (HIV) protease inhibitor and β3- adenergic receptor agonist
Nogami, Hiroyuki,Kanai, Motomu,Shibasaki, Masakatsu
, p. 702 - 709 (2007/10/03)
Chiral building block syntheses of promising drugs were achieved using two types of catalytic stereoselective cyanosilylations of aldehydes promoted by Lewis acid-Lewis base bifunctional catalysts 1 and 2 as the key steps (diastereoselective cyanosilylation of amino aldehyde and enantioselective cyanosilylation). In the first part of this article, syntheses of chiral building blocks (6) of Atazanavir (3: human immunodeficiency virus (HIV) protease inhibitor) using the bifunctional catalyst 2 are discussed. The reaction of Boc-protected phenylalaninal 21 in the presence of 1 mol% catalyst 2 selectively afforded the anti isomer 22 as the major product (diastereomeric ratio=97:3), which was successively converted to the corresponding epoxide 6 in six steps. In the second part, we describe a chiral building block synthesis of β3-adrenergic receptor agonists. The enantioselective cyanosilylation of 3-chlorobenzaldehyde (38) with 9 mol% catalyst 1 gave the chiral cyanohydrin 39, which was converted to β-hydroxyethylamine 40 by reduction. Moreover, the chiral ligand of catalyst 1 could be recovered without column chromatography and reused without decreasing its activity.
Process for producing optically active threo-3-amino-1,2-epoxy compounds
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, (2008/06/13)
Highly pure optically active threo-3-amino-1,2-epoxy compounds appropriate for materials for manufacturing drugs and a process for producing the same on an industrial scale. An optically active threo-3-amino-1,2-diol derivative is subjected in an organic solvent in the presence of a base to alkylsufonylation or arylsulfonylation to thereby give the corresponding optically active threo-3-amino-2-hydroxy-1-sulfonyloxy compound. Next, the resultant product is subjected to epoxidation in the presence of a base to give the corresponding optically active threo-3-amino-1,2-epoxy compound. The thus obtained epoxy compound is purified by using an organic solvent and water, thus giving a highly pure epoxy compound.
Highly convergent stereoselective synthesis of chiral key intermediates in the synthesis of Palinavir from imines derived from L-glyceraldehyde
Badorrey, Ramón,Cativiela, Carlos,Díaz-De-Villegas, María D,Gálvez, José A
, p. 341 - 354 (2007/10/03)
Imines derived from O-protected (S)-glyceraldehyde are valuable intermediates in the synthesis of different kinds of amino acids. We have developed a highly convergent and stereoselective method to obtain (2S,3S)-N-tert-butoxycarbonyl-1-phenyl-3,4-epoxy-2-butylamine and (2S,4R)-N-tert-butoxycarbonyl-4-hydroxypipecolic acid tert-butylamide, which are key intermediates in the synthesis of Palinavir, that consist in the treatment of the appropriate imine with benzylmagnesium bromide and Danishefsky's diene, respectively, and subsequent transformation of the obtained adducts into the desired compounds. The reaction of N-benzylimine derived from (S)-2,3-di-O-benzylglyceraldehyde with benzylmagnesium bromide is completely diastereoselective at low temperature. Hetero Diels-Alder reaction of imine derived from (S)-2,3-di-O-benzylglyceraldehyde and (R)-N-α-methylbenzylamine is completely diastereoselective at low temperature in the presence of ZnI2.
Transition-state mimetics for HIV protease inhibitors: Stereocontrolled synthesis of hydroxyethylene and hydroxyethylamine isosteres by ester- derived titanium enolate syn and anti-aldol reactions
Ghosh,Fidanze
, p. 6146 - 6152 (2007/10/03)
Stereocontrolled syntheses of hydroxyethylene dipeptide isostere and aminoalkyl epoxides for hydroxyethylamine isosteres are described. The stereochemistry of both stereogenic centers of the aminoalkyl epoxides 10 and 15 as well as they γ-lactone 17 was assembled by our recently developed highly selective ester-derived titanium enolate aldol reactions. The Ti- enolate of 6 reacted with (benzyloxy)acetaldehyde and cinnamaldehyde to provide the syn-aldol product 7 and anti-aldol product 12, respectively. Removal of the chiral template followed by Curtius rearrangement of the resulting acid provided the desired amine functionality. The present syntheses represent practical and enantioselective entry to a range of other dipeptide isosteres, which are not limited to amino acid derived substituents.
New approaches to the asymmetric synthesis of dipeptide isosteres via β-Lactam Synthon Method
Ojima, Iwao,Wang, Hong,Wang, Tao,Ng, Edward W.
, p. 923 - 926 (2007/10/03)
New and efficient synthetic routes to dipeptide isosteres with high enantiomeric purity, e.g., hydroxyethylene, dihydroxyethylene and hydroxyethylamine isosteres, have been developed via oxiranes 6 and formyloxazolines 13 derived from N-t-Boc-β-lactams 4.
A convenient synthesis of 1-(S)-[1'-(S)-(t-butyloxycarbonylamino)-2'- phenylethyl]oxirane. A useful building block in the synthesis of HIV protease inhibitors
Branalt, Jonas,Kvarnstroem, Ingemar,Classon, Bjoern,Samuelsson, Bertil,Nillroth, Ulrika,Danielson, U. Helena,Karlen, Anders,Hallberg, Anders
, p. 3483 - 3486 (2007/10/03)
A new short route to epoxide 6b, a pivotal intermediate for the preparation of hydroxyethylamine dipeptide isosteres has been developed. Opening of the epoxide by anthranilic acid, followed by extensions in the P2/P3-region gave the target compounds which were evaluated as HIV-1 protease inhibitors.
