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Chirality in Drug Discovery

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 October 2021) | Viewed by 32053

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Prof. Dr. Quezia Bezerra Cass

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Chemistry Department, Federal University of São Carlos, São Carlos, SP, Brazil
Interests: 2D LC for separation of chiral and achiral drugs; chiral screening technologies; bioanalysis; preparative chiral separation; immobilized enzymes for ligand screening assay from synthetic and natural libraries

Special Issue Information

Dear Colleagues,

Chirality is ubiquitous in nature and due to its effect on pharmacological properties, toxicity, and metabolism, it is of the utmost importance in drug discovery programs. In this regard, it encompasses enantioselective synthesis, chiral drug design and development, natural scaffolds, synthetic and natural libraries, biomarkers, chiral materials, enantiomeric separation, and methods to stereochemical elucidation. This Special Issue will cover all main aspects of chirality involved in drug discovery. The issue will publish original research articles, critical reviews, perspectives, and mini reviews from renowned researchers from academia and industry.

Prof. Dr. Quezia Bezerra Cass
Guest Editor

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Keywords

molecular modeling studies
chiral metabolomics
enantioselective analysis
asymmetric synthesis
enantioselective metabolism
chiroptical methods
enantioselective toxicity
X-ray crystallography
chiral screening technologies

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Published Papers (7 papers)

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Research

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14 pages, 2516 KiB

Open AccessArticle

Quality by Design Assisted Optimization of a Chiral Capillary Electrokinetic Chromatographic Method for the Separation of Amlodipine Enantiomers Using Maltodextrin as Chiral Selector

by Ratih Ratih, Hermann Wätzig, Matthias Oliver Stein and Sami El Deeb

Pharmaceuticals 2022, 15(3), 319; https://doi.org/10.3390/ph15030319 - 7 Mar 2022

Cited by 2 | Viewed by 2279

Abstract

Analytical-method development based on design of experiment has been applied for optimizing the enantioseparation of amlodipine by chiral capillary electrokinetic chromatography using maltodextrin as the chiral selector. The effect of different factors on the enantioresolution quality was screened. Three separation factors, namely maltodextrin concentration, pH of the background electrolyte and applied voltage were selected as independent variables. The number of experiments was reduced while maximizing the information content using design of experiment. Based on a full-quadratic design that included three variables on three levels, the total design space could be reduced to fifteen factor combinations using a D-optimal algorithm. The aim of the experiment was to find the optimal factor combinations with respect to resolution. The maltodextrin concentration (7.5–10% w/v) demonstrated the strongest effect on the resolution followed by pH (2–4) of the background electrolyte and the applied voltage (15–20 kV). An increase in the maltodextrin concentration was found to result in a greater stereoselectivity, represented by the higher resolution values (R_s ≥ 1.5). The separation conditions in the proposed method were feasible to be adjusted within the applied range with an acceptable resolution. Full article

(This article belongs to the Special Issue Chirality in Drug Discovery)

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Figure 1
Representative enantioseparation of AML at the shortest and longest analysis time. Full article ">Figure 2
The adjusted response graph of resolution (A) and Pareto chart of the effects of variables on resolution (B). MD: maltodextrin concentration (% w/v); U: voltage (kV). Full article ">Figure 3
Interaction graph for resolution at low, middle, and high levels. MD: maltodextrin concentration (% w/v); U: voltage (kV). Full article ">Figure 4
Contour plot of the predicted Rs at the respective combinations. Full article ">Figure 5
Enantioseparation profiles of amlodipine at the experimental condition MD 10% w/v (high), pH 2.0 (low), and voltage 15 kV (330 V/cm) for a 45.5 cm capillary (low). Peak identification shows that the migration order of amlodipine is the (S)-enantiomer followed by the (R)-enantiomer. Full article ">Figure 6
Enantioseparation profile of amlodipine in tablet matrices at the experimental condition MD 10% w/v (high), pH 2.0 (low), and voltage 15 kV (330 V/cm) for a 45.5 cm capillary (low). Full article ">

11 pages, 1646 KiB

Open AccessArticle

The Separation of Cannabinoids on Sub-2 µm Immobilized Polysaccharide Chiral Stationary Phases

by Takafumi Onishi and Weston J. Umstead

Pharmaceuticals 2021, 14(12), 1250; https://doi.org/10.3390/ph14121250 - 30 Nov 2021

Cited by 12 | Viewed by 3581

Abstract

The increased use and applicability of Cannabis and Cannabis-derived products has skyrocketed over the last 5 years. With more and more governing bodies moving toward medical and recreational legalization, the need for robust and reliable analytical testing methods is also growing. While many stationary phases and methods have been developed for this sort of analysis, chiral stationary phases (CSPs) are unique in this area; not only can they serve their traditional chiral separation role, but they can also be used to perform achiral separations. Given that mixtures of cannabinoids routinely contain enantiomers, diastereomers, and structural isomers, this offers an advantage over the strictly achiral-only analyses. This work presents the separation of a 10-cannabinoid mixture on several polysaccharide-based sub-2 µm CSPs with both normal-phase and reversed-phase ultra-high-performance liquid chromatography (UHPLC) conditions. Along with the separation of the mixture, appropriate single-peak identification was performed to determine the elution order and reported where applicable. Full article

(This article belongs to the Special Issue Chirality in Drug Discovery)

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24 pages, 4312 KiB

Open AccessArticle

Enantioselectivity of Chiral Derivatives of Xanthones in Virulence Effects of Resistant Bacteria

by Fernando Durães, Sara Cravo, Joana Freitas-Silva, Nikoletta Szemerédi, Paulo Martins-da-Costa, Eugénia Pinto, Maria Elizabeth Tiritan, Gabriella Spengler, Carla Fernandes, Emília Sousa and Madalena Pinto

Pharmaceuticals 2021, 14(11), 1141; https://doi.org/10.3390/ph14111141 - 10 Nov 2021

Cited by 6 | Viewed by 2753

Abstract

Antimicrobial peptides are one of the lines of defense produced by several hosts in response to bacterial infections. Inspired by them and recent discoveries of xanthones as bacterial efflux pump inhibitors, chiral amides with a xanthone scaffold were planned to be potential antimicrobial adjuvants. The chiral derivatives of xanthones were obtained by peptide coupling reactions between suitable xanthones with enantiomerically pure building blocks, yielding derivatives with high enantiomeric purity. Among 18 compounds investigated for their antimicrobial activity against reference strains of bacteria and fungi, antibacterial activity for the tested strains was not found. Selected compounds were also evaluated for their potential to inhibit bacterial efflux pumps. Compound (R,R)-8 inhibited efflux pumps in the Gram-positive model tested and three compounds, (S,S)-8, (R)-17 and (R,S)-18, displayed the same activity in the Gram-negative strain used. Studies were performed on the inhibition of biofilm formation and quorum-sensing, to which the enantiomeric pair 8 displayed activity for the latter. To gain a better understanding of how the active compounds bind to the efflux pumps, docking studies were performed. Hit compounds were proposed for each activity, and it was shown that enantioselectivity was noticeable and must be considered, as enantiomers displayed differences in activity. Full article

(This article belongs to the Special Issue Chirality in Drug Discovery)

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Graphical abstract
Full article ">Figure 1
Chromatograms for the enantioseparation of the enantiomeric mixture 16, at optimized chromatographic conditions. Full article ">Figure 2
Comparison of the RFI of different compounds to those of the positive controls [S. aureus 272123 (top); SE03 (bottom)]. Results are presented as mean ± SD. Statistical comparisons were performed using the t-test [* p < 0.05; ** p < 0.01 vs. control (DMSO 1% v/v)]. Full article ">Figure 2 Cont.
Comparison of the RFI of different compounds to those of the positive controls [S. aureus 272123 (top); SE03 (bottom)]. Results are presented as mean ± SD. Statistical comparisons were performed using the t-test [* p < 0.05; ** p < 0.01 vs. control (DMSO 1% v/v)]. Full article ">Figure 3
Molecular visualization of (R,R)-8 (blue) and (S,S)-8 (pink) in the BCR of the homology model of NorA; (A) interaction of (R,R)-8 with key residues; (B) surface view of (R,R)-8 inside a pocket; (C) visualization of (S,S)-8 at the surface of the homology model. Full article ">Figure 3 Cont.
Molecular visualization of (R,R)-8 (blue) and (S,S)-8 (pink) in the BCR of the homology model of NorA; (A) interaction of (R,R)-8 with key residues; (B) surface view of (R,R)-8 inside a pocket; (C) visualization of (S,S)-8 at the surface of the homology model. Full article ">Figure 4
Molecular visualization of the effective compounds in the SBS of AcrB. (A) (R,R)-8 (yellow) and (S,S)-8 (pink) in the SBS of AcrB; (B) interactions of (S,S)-8 with key residues; (C) interactions of (R)-17 with key residues; (D) interactions of (R,S)-18 with key residues; (E) interactions of doxorubicin with key residues. Full article ">Scheme 1
Synthetic pathways for obtaining 3,4-substituted chiral derivatives of xanthones used in this study. (i) AlCl3, anhydrous toluene, 70 °C, 40 min; (ii) BrCH2COOCH3, K2CO3, anhydrous acetone, 4–24 h; (iii) NaOH 5M, CH2Cl2:CH3OH (1:1 v/v), rt, 5–24 h; (iv) (R)-(−) or (S)-(+)-2-phenylglycinol, TBTU, anhydrous THF, TEA, rt, 5 h; (v) (R)-(+) or (S)-(−)-(α)-methylbenzylamine, TBTU, TEA, anhydrous THF, 2 h; (vi) BrCH2CH2OH, NaH, anhydrous acetone, reflux, 14 h. Full article ">Scheme 2
Synthetic pathways for obtaining 2,6-substituted chiral derivatives of xanthones used in this study. (i) NaOH 5M, CH2Cl2:CH3OH (1:1 v/v), rt, 5–22 h; (ii) (R)-(+) or (S)-(−)-(α)-methylbenzylamine, TBTU, anhydrous THF, TEA, rt, 1 h; (iii) Et2NCH2SH.HCl, NaOtBu, anhydrous DMF, reflux, N2, 4 h (iv) BrCH2COOCH3, K2CO3, anhydrous acetone, 3 h; (v) (S)-(−) or (R)-(+)-2-phenylglycinol, TBTU, anhydrous THF, TEA, rt, 3 h. Full article ">

14 pages, 5534 KiB

Open AccessArticle

Asymmetric Total Syntheses of Both Enantiomers of Plymuthipyranone B and Its Unnatural Analogues: Evaluation of anti-MRSA Activity and Its Chiral Discrimination

by Mizuki Moriyama, Xiaoxi Liu, Yuki Enoki, Kazuaki Matsumoto and Yoo Tanabe

Pharmaceuticals 2021, 14(9), 938; https://doi.org/10.3390/ph14090938 - 19 Sep 2021

Cited by 2 | Viewed by 2612

Abstract

Chiral total syntheses of both enantiomers of the anti-MRSA active plymuthipyranone B and all of the both enantiomers of three unnatural and synthetic analogues were performed. These two pairs of four chiral compounds are composed of the same 3-acyl-5,6-dihydro-2H-pyran-2-one structure. The starting synthetic step utilized a privileged asymmetric Mukaiyama aldol addition using Ti(OiPr)₄/(S)-BINOL or Ti(OiPr)₄/(R)-BINOL catalysis to afford the corresponding (R)- and (S)-?-hydroxy-?-ketoesters, respectively, with highly enantiomeric excess (>98%). Conventional lactone formation and successive EDCI-mediated C-acylation produced the desired products, (R)- and (S)-plymuthipyranones B and three (R)- and (S)- synthetic analogues, with an overall yield of 42–56% with a highly enantiomeric excess (95–99%). A bioassay of the anti-MRSA activity against ATCC 43300 and 33591 revealed that (i) the MICs of the synthetic analogues against ATCC 43300 and ATCC 33591 were between 2 and 16 and 4 and 16 ?g/mL, respectively, and those of vancomycin (reference) were 1 ?g/mL. (ii) The natural (S)-plymuthipyranone B exhibited significantly higher activity than the unnatural (R)-antipode against both AACCs. (iii) The natural (R)-plymuthipyranone B and (R)-undecyl synthetic analogue at the C6 position exhibited the highest activity. The present work is the first investigation of the SAR between chiral R and S forms of this chemical class. Full article

(This article belongs to the Special Issue Chirality in Drug Discovery)

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Review

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29 pages, 4020 KiB

Open AccessReview

Chiral Flavonoids as Antitumor Agents

by Cláudia Pinto, Honorina Cidade, Madalena Pinto and Maria Elizabeth Tiritan

Pharmaceuticals 2021, 14(12), 1267; https://doi.org/10.3390/ph14121267 - 5 Dec 2021

Cited by 26 | Viewed by 5060

Abstract

Flavonoids are a group of natural products with a great structural diversity, widely distributed in plant kingdom. They play an important role in plant growth, development and defense against aggressors. Flavonoids show a huge variety of biological activities such as antioxidant, anti-inflammatory, anti-mutagenic, antimicrobial and antitumor, being able to modulate a large diversity of cellular enzymatic activities. Among natural flavonoids, some classes comprise chiral molecules including flavanones, flavan-3-ols, isoflavanones, and rotenoids, which have one or more stereogenic centers. Interestingly, in some cases, individual compounds of enantiomeric pairs have shown different antitumor activity. In nature, these compounds are mainly biosynthesized as pure enantiomers. Nevertheless, they are often isolated as racemates, being necessary to carry out their chiral separation to perform enantioselectivity studies. Synthetic chiral flavonoids with promising antitumor activity have also been obtained using diverse synthetic approaches. In fact, several new chiral bioactive flavonoids have been synthesized by enantioselective synthesis. Particularly, flavopiridol was the first cyclin-dependent kinase (CDK) inhibitor which entered clinical trials. The chiral pool approaches using amino acid as chiral building blocks have also been reported to achieve small libraries of chrysin derivatives with more potent in vitro growth inhibitory effect than chrysin, reinforcing the importance of the introduction of chiral moieties to improve antitumor activity. In this work, a literature review of natural and synthetic chiral flavonoids with antitumor activity is reported for the first time. Full article

(This article belongs to the Special Issue Chirality in Drug Discovery)

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18 pages, 21714 KiB

Open AccessFeature PaperReview

Advances on Greener Asymmetric Synthesis of Antiviral Drugs via Organocatalysis

by Everton M. da Silva, Hérika D. A. Vidal and Arlene G. Corrêa

Pharmaceuticals 2021, 14(11), 1125; https://doi.org/10.3390/ph14111125 - 4 Nov 2021

Cited by 5 | Viewed by 5040

Abstract

Viral infections cause many severe human diseases, being responsible for remarkably high mortality rates. In this sense, both the academy and the pharmaceutical industry are continuously searching for new compounds with antiviral activity, and in addition, face the challenge of developing greener and more efficient methods to synthesize these compounds. This becomes even more important with drugs possessing stereogenic centers as highly enantioselective processes are required. In this minireview, the advances achieved to improve synthetic routes efficiency and sustainability of important commercially antiviral chiral drugs are discussed, highlighting the use of organocatalytic methods. Full article

(This article belongs to the Special Issue Chirality in Drug Discovery)

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25 pages, 6355 KiB

Open AccessFeature PaperReview

Tackling Stereochemistry in Drug Molecules with Vibrational Optical Activity

by Jonathan Bogaerts, Roy Aerts, Tom Vermeyen, Christian Johannessen, Wouter Herrebout and Joao M. Batista

Pharmaceuticals 2021, 14(9), 877; https://doi.org/10.3390/ph14090877 - 29 Aug 2021

Cited by 21 | Viewed by 8255

Abstract

Chirality plays a crucial role in drug discovery and development. As a result, a significant number of commercially available drugs are structurally dissymmetric and enantiomerically pure. The determination of the exact 3D structure of drug candidates is, consequently, of paramount importance for the pharmaceutical industry in different stages of the discovery pipeline. Traditionally the assignment of the absolute configuration of druggable molecules has been carried out by means of X-ray crystallography. Nevertheless, not all molecules are suitable for single-crystal growing. Additionally, valuable information about the conformational dynamics of drug candidates is lost in the solid state. As an alternative, vibrational optical activity (VOA) methods have emerged as powerful tools to assess the stereochemistry of drug molecules directly in solution. These methods include vibrational circular dichroism (VCD) and Raman optical activity (ROA). Despite their potential, VCD and ROA are still unheard of to many organic and medicinal chemists. Therefore, the present review aims at highlighting the recent use of VOA methods for the assignment of the absolute configuration of chiral small-molecule drugs, as well as for the structural analysis of biologics of pharmaceutical interest. A brief introduction on VCD and ROA theory and the best experimental practices for using these methods will be provided along with selected representative examples over the last five years. As VCD and ROA are commonly used in combination with quantum calculations, some guidelines will also be presented for the reliable simulation of chiroptical spectra. Special attention will be paid to the complementarity of VCD and ROA to unambiguously assess the stereochemical properties of pharmaceuticals. Full article

(This article belongs to the Special Issue Chirality in Drug Discovery)

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