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Medicinal Chemistry (Shariqah (United... 2020Numerous synthetic bile acid derivatives have been recognized for their various biological activities. Among these, bile acid amides have emerged as an attractive...
BACKGROUND
Numerous synthetic bile acid derivatives have been recognized for their various biological activities. Among these, bile acid amides have emerged as an attractive antibacterial agent. We herein illustrate the synthesis and antibacterial evaluation of deoxycholic acidamino alcohols conjugates.
OBJECTIVE
Design and Synthesis of novel deoxycholic acid-amino alcohol conjugates to investigate their antibacterial activity against E. coli and S. aureus.
METHODS
Novel deoxycholic acid-amino alcohol conjugates were synthesized, from conjugation of deoxycholic acid-NHS ester with amino alcohols. Various amino alcohols moieties were appended to the C24 position of deoxycholic acid to yield deoxycholic acid-amino alcohol conjugates. All the synthesized compounds were characterized by 1H NMR, 13C NMR, IR and massspectroscopy. The entire synthesized deoxycholic acid-amino alcohol conjugates were evaluated for their antibacterial activity against E. coli and S. aureus using the broth dilution method.
RESULTS
The outcome illustrated that some of the novel deoxycholic acid-amino alcohol conjugates exhibited enhanced anti-bacterial activities. Amongst them, deoxycholic acid-amino alcohol conjugate containing (-R)-2-aminocyclohexanol (1) demonstrated promising efficacy against both strains S. aureus ATCC 25923 (MIC 15 μg/mL) and E. coli ATCC 25922 (MIC 45 μg/mL) and was identified as a lead molecule.
CONCLUSION
Numbers of novel deoxycholic acid-amino alcohol conjugates were synthesized and their antimicrobial activities provided useful information that the potency was strongly depending on the structures of deoxycholic acid-amino alcohol conjugates.
Topics: Amino Alcohols; Anti-Bacterial Agents; Deoxycholic Acid; Drug Design; Escherichia coli; Microbial Sensitivity Tests; Molecular Structure; Staphylococcus aureus; Structure-Activity Relationship
PubMed: 30727909
DOI: 10.2174/1573406415666190206231002 -
Molecules (Basel, Switzerland) Feb 2020In this report, we describe the synthetic elaboration of the easily available enantiomerically pure β-amino alcohols. Attempted direct substitution of the hydroxyl...
In this report, we describe the synthetic elaboration of the easily available enantiomerically pure β-amino alcohols. Attempted direct substitution of the hydroxyl group by azido-functionality in the Mitsunobu reaction with hydrazoic acid was inefficient or led to a diastereomeric mixture. These outcomes resulted from the participation of aziridines. Intentionally performed internal Mitsunobu reaction of β-amino alcohols gave eight chiral aziridines in 45-82% yield. The structural and configuration identity of products was confirmed by NMR data compared to the DFT calculated GIAO values. For 1,2,3-trisubstituted aziridines slow configurational inversion at the endocyclic nitrogen atom was observed by NMR at room temperature. Moreover, when aziridine was titrated with Zn(OAc) under NMR control, only one of two N-epimers directly participated in complexation. The aziridines underwent ring opening with HN to form the corresponding azido amines as single regio- and diastereomers in 90-97% yield. Different results were obtained for 1,2-disubstituted and 1,2,3-trisubstituted aziridines. For the later aziridines ring closure and ring opening occurred at different carbon stereocenters, thus yielding products with two inverted configurations, compared to the starting amino alcohol. The 1,2-disubstituted aziridines produced azido amines of the same configuration as the starting β-amino alcohols. To obtain a complete series of diastereomeric -diamines, we converted the amino alcohols into cyclic sulfamidates, which reacted with sodium azide in S2 reaction (25-58% overall yield). The azides obtained either way underwent the Staudinger reduction, giving a series of six new chiral -diamines of defined stereochemistries.
Topics: 2,2'-Dipyridyl; Amines; Amino Alcohols; Azides; Aziridines; Diamines; Magnetic Resonance Spectroscopy; Molecular Structure; Stereoisomerism
PubMed: 32046110
DOI: 10.3390/molecules25030727 -
Chirality Jun 2022Chiral separation of β-blockers is performed by utilizing the supercritical fluid chromatographic method. The chiral columns utilized were Chiralpak IG and Chiralpak... (Review)
Review
Chiral separation of β-blockers is performed by utilizing the supercritical fluid chromatographic method. The chiral columns utilized were Chiralpak IG and Chiralpak IBN-5. The finest mobile phase was CO -0.2% TEA in methanol (60:40). The values atenolol enantiomers retention factors were 6.39 and 8.98. These values for propranolol enantiomers were 3.39 and 4.06. These values for betaxolol enantiomers were 4.08 and 4.68. The separation and resolution factor values for atenolol, propranolol, and betaxolol were 1.41 and 3.33, 1.19 and 2.23, and 1.15 and 1.87, separately and respectively. By comparison, it was observed that Chiralpak IG column is better than Chiralpak IBN-5 column. Supercritical fluid chromatography has been found as the best analytical technique due to its high speed, being eco-friendly, and being economic. The various most probable interactions responsible for the chiral resolution are hydrogen bonding, dipole-dipole interactions, steric effect, and π-π interactions. The reported methods are effective, efficient, and reproducible and may be used to separate and identify atenolol, propranolol, and betaxolol in any unknown samples.
Topics: Adrenergic beta-Antagonists; Atenolol; Betaxolol; Chromatography, Supercritical Fluid; Propranolol; Stereoisomerism
PubMed: 35297109
DOI: 10.1002/chir.23440 -
The Journal of Organic Chemistry Sep 2018Chiral 1,2-amino alcohols are privileged scaffolds with important applications as drug candidates and chiral ligands. Although various methods for the preparation of...
Chiral 1,2-amino alcohols are privileged scaffolds with important applications as drug candidates and chiral ligands. Although various methods for the preparation of this structural motif have been reported, these methods are limited because of the use of precious metals and ligands. Here, we report a practical and high yielding synthesis of chiral 1,2-amino alcohols using arylglyoxals and pseudoephedrine auxiliary. This reaction is catalyzed by a Brønsted acid and provides morpholinone products in high yields and selectivities. The morpholine ring was converted into 1,2-amino alcohols in a two-step protocol.
Topics: Amino Alcohols; Chemistry Techniques, Synthetic; Glyoxal; Morpholines; Stereoisomerism
PubMed: 30039699
DOI: 10.1021/acs.joc.8b01516 -
Organic Letters Nov 2019Asymmetric synthesis of γ-amino alcohols from unprotected allylic alcohols by a copper-catalyzed hydroamination strategy has been developed. Using easily accessible...
Asymmetric synthesis of γ-amino alcohols from unprotected allylic alcohols by a copper-catalyzed hydroamination strategy has been developed. Using easily accessible starting materials, a range of chiral 1,3-amino alcohols were prepared with excellent regio- and enantioselectivity. Further, this protocol provided an efficient one-step method for the enantioselective synthesis of γ-amino alcohols in an intermolecular manner.
Topics: Amination; Amino Alcohols; Catalysis; Chemistry Techniques, Synthetic; Copper
PubMed: 31625750
DOI: 10.1021/acs.orglett.9b03356 -
Journal of Enzyme Inhibition and... Dec 2023Carbonic anhydrases (CAs) are widespread metalloenzymes which catalyse the reversible hydration of carbon dioxide (CO) to bicarbonate (HCO) and a proton, relevant in...
Carbonic anhydrases (CAs) are widespread metalloenzymes which catalyse the reversible hydration of carbon dioxide (CO) to bicarbonate (HCO) and a proton, relevant in many physiological processes. In the last few years, the involvement of CA activation in different metabolic pathways in the human brain addressed the research to the discovery of novel CA activators. Here, a new series of isoxazoline-based amino alcohols as CA activators was investigated. The synthesis and the CA activating effects towards four human CA isoforms expressed in the human brain, that are hCAs I, II, IV and VII, were reported. The best results were obtained for the (methyl)-isoxazoline-amino alcohols and with K values in the submicromolar range (0.52-0.86 µM) towards hCA VII, and a good selectivity over hCA I. Being hCA VII involved in brain function and metabolism, the newly identified CA activators might be promising hit compounds with potential therapeutic applications in ageing, epilepsy or neurodegeneration.
Topics: Humans; Carbonic Anhydrases; Molecular Structure; Carbonic Anhydrase Inhibitors; Amines; Brain; Amino Alcohols; Structure-Activity Relationship
PubMed: 36630083
DOI: 10.1080/14756366.2022.2164574 -
Biotechnology and Bioengineering Mar 2018Rapid biocatalytic process development and intensification continues to be challenging with currently available methods. Chiral amino-alcohols are of particular interest...
Rapid biocatalytic process development and intensification continues to be challenging with currently available methods. Chiral amino-alcohols are of particular interest as they represent key industrial synthons for the production of complex molecules and optically pure pharmaceuticals. (2S,3R)-2-amino-1,3,4-butanetriol (ABT), a building block for the synthesis of protease inhibitors and detoxifying agents, can be synthesized from simple, non-chiral starting materials, by coupling a transketolase- and a transaminase-catalyzed reaction. However, until today, full conversion has not been shown and, typically, long reaction times are reported, making process modifications and improvement challenging. In this contribution, we present a novel microreactor-based approach based on free enzymes, and we report for the first time full conversion of ABT in a coupled enzyme cascade for both batch and continuous-flow systems. Using the compartmentalization of the reactions afforded by the microreactor cascade, we overcame inhibitory effects, increased the activity per unit volume, and optimized individual reaction conditions. The transketolase-catalyzed reaction was completed in under 10 min with a volumetric activity of 3.25 U ml . Following optimization of the transaminase-catalyzed reaction, a volumetric activity of 10.8 U ml was attained which led to full conversion of the coupled reaction in 2 hr. The presented approach illustrates how continuous-flow microreactors can be applied for the design and optimization of biocatalytic processes.
Topics: Amino Alcohols; Aminoacyltransferases; Catalysis; Escherichia coli; Escherichia coli Proteins; Transketolase
PubMed: 28986983
DOI: 10.1002/bit.26470 -
ChemistryOpen Jun 2022A new racemic naphthyl-coumarin-based probe was found to bind covalently with amino acids in MeOH-KOH system and thereby generates distinct CD responses. The induced...
A new racemic naphthyl-coumarin-based probe was found to bind covalently with amino acids in MeOH-KOH system and thereby generates distinct CD responses. The induced strong CD signals allowed quantitative enantiomeric excess analysis of amino acids and enantioselective sensing of amines and amino alcohols. The mechanism for the reaction of the coumarin-aldehyde probe with an amino acid was investigated by CD, UV-Vis, NMR, ESI-MS analyses and ECD calculation.
Topics: Amines; Amino Acids; Amino Alcohols; Coumarins; Stereoisomerism
PubMed: 35642171
DOI: 10.1002/open.202200088 -
Nature Communications Jun 2016New types of asymmetric functionalizations of alkenes are highly desirable for chemical synthesis. Here, we develop three novel types of regio- and enantioselective...
New types of asymmetric functionalizations of alkenes are highly desirable for chemical synthesis. Here, we develop three novel types of regio- and enantioselective multiple oxy- and amino-functionalizations of terminal alkenes via cascade biocatalysis to produce chiral α-hydroxy acids, 1,2-amino alcohols and α-amino acids, respectively. Basic enzyme modules 1-4 are developed to convert alkenes to (S)-1,2-diols, (S)-1,2-diols to (S)-α-hydroxyacids, (S)-1,2-diols to (S)-aminoalcohols and (S)-α-hydroxyacids to (S)-α-aminoacids, respectively. Engineering of enzyme modules 1 &2, 1 &3 and 1, 2 &4 in Escherichia coli affords three biocatalysts over-expressing 4-8 enzymes for one-pot conversion of styrenes to the corresponding (S)-α-hydroxyacids, (S)-aminoalcohols and (S)-α-aminoacids in high e.e. and high yields, respectively. The new types of asymmetric alkene functionalizations provide green, safe and useful alternatives to the chemical syntheses of these compounds. The modular approach for engineering multi-step cascade biocatalysis is useful for developing other new types of one-pot biotransformations for chemical synthesis.
Topics: Alkenes; Amino Acids; Amino Alcohols; Biocatalysis; Escherichia coli; Models, Chemical; Molecular Structure; Stereoisomerism; Styrenes
PubMed: 27297777
DOI: 10.1038/ncomms11917 -
Angewandte Chemie (International Ed. in... Oct 2022The combination of small-molecule catalysis and enzyme catalysis represents an underexploited area of research with huge potential in asymmetric synthetic chemistry due...
The combination of small-molecule catalysis and enzyme catalysis represents an underexploited area of research with huge potential in asymmetric synthetic chemistry due to both compatibility of reaction conditions and complementary reactivity. Herein, we describe the telescopic synthesis of chiral nitro alcohols starting from commercially available benzaldehyde derivatives through the one-pot three-step chemoenzymatic cascade combination of a Wittig reaction, chiral-thiourea-catalysed asymmetric conjugate addition, and ketoreductase-mediated reduction to access the corresponding target compounds in moderate to excellent overall isolated yields (36-80 %) and high diastereomeric and enantiomeric ratios (up to >97 : 3). This represents the first example of the combination of an organocatalysed asymmetric conjugate addition via iminium ion activation and a bioreduction step catalysed by ketoreductases.
Topics: Alcohols; Amino Alcohols; Benzaldehydes; Biocatalysis; Catalysis; Stereoisomerism; Thiourea
PubMed: 35983936
DOI: 10.1002/anie.202209159