Achiral Drug Research Articles

The association of chiral characteristic with drug withdrawal due to safety: A comparative analysis.

Chirality of drugs might be associated with safety issues through pharmacokinetic or pharmacodynamic variations, interactions, or direct toxicological responses. We aimed to compare chiral status of the available drugs to that of drugs withdrawn due to adverse drug reactions (ADRs). We searched the literature regarding withdrawn drugs due to safety-related issues (n =391) to compare them with all available small-molecule drugs (n =1633). We examined their chiral status and assigned as achiral compound, chiral mixture or pure enantiomer. We compared the mean survival (i.e., nonwithdrawal) time and withdrawal rates of drugs by their chirality, with further stratification by the launch year, ATC-1 (Anatomical Therapeutic Chemical) level and ADR. We identified higher withdrawal rate in achiral drugs (hazard ratio 2.1, 95% CI: 1.6-2.7) and chiral mixtures (hazard ratio 2.6, 95% CI: 1.9-3.5) compared to that in pure enantiomers. Pure enantiomers had the longest mean survival time (62.4±0.8years), followed by achiral drugs (55.4±0.9years, P< .01) and chiral mixtures (52.4±1.4years, P< .01). Pure enantiomers had higher survival rates than chiral mixtures if launched before 1941 (P= .02), in 1961-1980 (P< .001) or 1981-2000 (P< .001). Pure enantiomers had lower withdrawal rate (18.2%) vs. chiral mixtures (35.1%, P= .02) in nervous system drugs. Pure enantiomers had lower withdrawal rate than chiral mixtures in hepatotoxic (P< .01) and cardiovascular ADRs (P< .01). Our study showed lower likelihood of withdrawal for pure enantiomers compared to that in chiral mixtures and achiral drugs, which was more remarkable for those launched in certain time periods and several ADRs, including hepatotoxicity and cardiovascular toxicity.

Contribution of molecular chiral mesoporous silica nanoparticles in delivering drugs with chiral recognition ability

Among massive study of mesoporous silica nanoparticles, molecular chiral mesoporous silica nanoparticles (MC-MSN) enjoy great interests recently as it may exert special functions in chiral environment. To elucidate its potential abilities as drug carriers, the present work focused on its prominent advantage of chiral recognition in adsorbing and delivering drug molecules, which mainly covered molecular recognition of racemic drugs and chiral delivery of achiral drug by triggering chiral responses in biological environment. The result turned out that the loading capacity of L-alanine was 1.56-fold higher than that of DL-alanine, reminding that MC-MSN had effective molecular recognition function due to its chirality. Furthermore, the peak area ratio of levorotary ofloxacin/dextral ofloxacin from loaded ofloxacin was obviously higher than ofloxacin, confirming that MC-MSN can molecularly recognize levorotary drug. After loading poorly water-soluble drug indometacin (IMC) into MC-MSN, the carrier delivered IMC with improved anti-inflammation effect based on its chiral recognition effect.

Synthesis and Investigation of Chiral Poly(2,4-disubstituted-2-oxazoline)-Based Triblock Copolymers, Their Self-Assembly, and Formulation with Chiral and Achiral Drugs

Considering the largely chiral nature of biological systems, there is interest in chiral drug delivery systems. Here, we investigate for the first time polymer micelles based on poly(2-oxazoline) (POx) ABA-type triblock copolymers with chiral and racemic hydrophobic blocks for the formulation of chiral and achiral drugs. Specifically, poly(2-ethyl-4-ethyl-2-oxazoline) (pEtEtOx) and poly(2-propyl-4-methyl-2-oxazoline) (pPrMeOx) were used as hydrophobic block B and poly(2-methyl-2-oxazoline) (pMeOx) as hydrophilic block A. Using these triblock copolymers, nanoformulations of curcumin (CUR), paclitaxel (PTX), and chiral (R and S) and racemic ibuprofen were prepared. For CUR and PTX, the maximum drug loading was significantly dependent on the structure of the hydrophobic repeat units, but not the chirality. In contrast, the maximum drug loading with chiral/racemic ibuprofen was affected neither by the polymer structure nor by chirality, but minor effects were observed with respect to the size and size distribution of the drug-loaded micelles.

A New Benzyl Phenethanolamine-β-Cyclodextrin Bonded Phase: Chiral Chromatography Performance and Application for LC-MS/MS Analysis of Pesticide Enantiomers in Fruits and Vegetables.

At present, the research on achiral drug and pesticide residue detection methods is still the mainstay at home and abroad, and there is still a lack of systematic research on the enantiomeric analysis of chiral drugs and pesticides. In order to prepare a novel chiral stationary phase, whose "multi-mode" chiral separation chromatographic performance and its utility was verified. An S-(-)-2-benzylamino-1-phenylethanol mono-derivative β-cyclodextrin bonded stationary phase (BzCSP) was prepared based on the "thiol-ene" addition reaction. The chiral compounds including four types of chiral compounds were used as "probes," and their chiral chromatographic properties were evaluated. Furthermore, a new LC-MS/MS method for the determination of the enantiomeric residues of three chiral pesticides in five kinds of fruits and vegetables was established. The study found that the novel stationary phase was suitable for a variety of chromatographic modes (normal phase mode, reversed-phase mode, polar organic mode). The resolutions of hexaconazole (Hex), tebuconazole (Teb), and triticonazole (Trit) enantiomers could be up to 2.31, 1.68, and 1.48, respectively, within 30 min under reversed-phase chromatography. Based on the optimal chromatographic and mass spectrum conditions, a new LC-MS/MS quantitative method for the Hex, Teb, and Trit enantiomers was established by multi-reaction positive ion monitoring (MRM). The detection limits (LODs) of enantiomers were less than 0.89 µg/kg for Hex, 0.93 µg/kg for Teb, and 0.93 µg/kg for Trit, and the averaged recoveries of enantiomers were in the range of 75.8-106.3% for Hex, 77.4-116.3% for Teb, and 78.7-113.4% for Trit. The method had good reproducibility with the RSDs (<5%) for intraday and (<7%) for interday. The established method had the characteristics of good selectivity, high sensitivity, strong resistance to matrix interference, and good reproducibility. It is indicated that the stationary phase prepared by the "thiol-ene" addition reaction is a new type of multi-mode stationary phase, which has a good development value. The study reported a new method for the rapid preparation of a rare "multi-mode" chiral stationary phase BzCSP based on the "thiol-ene" addition reaction and verified the practicability of BzCSP including good selectivity, high sensitivity, strong resistance to matrix interference, and good reproducibility.

Occurrence and fate of chiral and achiral drugs in estuarine water - a case study of the Clyde Estuary, Scotland.

There is currently a lack of enantiospecific studies on chiral drugs in estuarine environments. In this study, the occurrence and fate of 20 prescription and illicit drugs, metabolites and associated contaminants were investigated in the Clyde Estuary, Scotland, over a 6 month period. More than half of the drugs were detected in at least 50% of water samples collected (n = 30), with considerable enantiomer enrichment observed for some of the compounds. Enantiomeric fraction (EF) values of the chiral drugs investigated in this study ranged from <0.03 for amphetamine to 0.70 for bisoprolol. Microcosm studies revealed enantioselective degradation of fluoxetine and citalopram for the first-time in estuarine waters (over 14 days at 8.0 °C in water of 27.8 practical salinity units). Interestingly, fish collected from the inner estuary (Platichthys flesus - European flounder) contained drug enantiomers in muscle and liver tissues. This included propranolol, fluoxetine, citalopram, and venlafaxine. Considerable enantiospecific differences were observed between the two fish tissues, and between fish tissues and water samples. For example, citalopram EF values in muscle and liver were 0.29 ± 0.03 and 0.18 ± 0.01, respectively. In water samples EF values were in the range 0.36-0.49. This suggests enantioselective metabolism of citalopram by P. flesus. The enantioselectivity of drugs observed within the Clyde Estuary highlights the need for enantiospecific effect-driven studies on marine organisms to better understand their impact in estuarine environments, contributing to the likely cumulative impacts of the range of contaminants to which marine coastal wildlife is exposed.

Alanine modified chiral-responsive mesoporous silica as nanocarriers for improved oral bioavailability of carvedilol

Alanine-modified chiral mesoporous silica (CMS) was firstly synthesized using chiral silane coupling agent (L-Ala-ICPTES or D-Ala-ICPTES) deriving from L-alanine or D-alanine, which was denoted as L-Ala-MSN and D-Ala-MSN, respectively. The as-prepared CMSs exhibited highly ordered mesoporous structure with spherical morphology, huge specific surface area and pore volume, successful modification of alanine and opposite chirality, which was identified by transmission electron microscope (TEM), small angle X-ray diffraction (SAXRD), nitrogen adsorption/desorption measurement, fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA) and induced circular dichroism (ICD). We also found that the biocompatibility of alanine modified CMSs was better than that of unmodified CMSs, which was confirmed by wettability test, degradation analysis, hemolysis test, protein adsorption test and evaluation of gastrointestinal irritation. Above all, the CMSs exerted chiral-selective delivery of achiral drug carvedilol (CAR) in simulated chiral environments. Pharmacokinetic studies revealed that L-Ala-MSN and D-Ala-MSN could significantly improve oral bioavailability of carvedilol (168.43% and 230.18% respectively), and D-Ala-MSN could delivery more drugs in vivo . This work has laid a theoretical foundation for rational design of chiral nano-drug delivery systems and promoted the application and development of CMSs in medicine. • CMSs were firstly obtained by chiral silane coupling agent deriving from L/D-alanine. • CMSs exhibited good biocompatibility and chiral-selective delivery of carvedilol. • CMSs had significantly improved the oral bioavailability of carvedilol.

Chiral microenvironment-responsive mesoporous silica nanoparticles for delivering indometacin with chiral recognition function

The purpose of this study was to investigate the potential chiral recognition functions induced by two kinds of novel chiral microenvironment-responsive mesoporous silica nanoparticles (CMR-L-MSN and CMR-D-MSN) for the oral delivery of the poorly water-soluble achiral drug indomethacin (IMC). The as-synthesized CMR-L-MSN and CMR-D-MSN with molecular chirality and high specific surface area (SBET: 1141 and 1075 m2/g, respectively) were successfully prepared through grafting chiral molecular functional groups. The characterization results showed that CMR-L-MSN and CMR-D-MSN were spherical nanoparticles with opposite chiral features and clearly visible pore channels. Meanwhile, they exhibited good biosafety and degradability. In vitro drug release study indicated that both CMR-L-MSN and CMR-D-MSN significantly improved IMC dissolution compared with naked-MSN (N-MSN) (p < 0.05) and exhibited different chiral recognition functions for drug release in the simulated chiral environments in vitro (pH 6.8 PBS-D/L), in which CMR-D-MSN could be triggered by the L-configurations in chiral environments and exhibited a better drug release effect. As expect, the results of in vivo biological effects disclosed that CMR-D-MSN had higher bioavailability of IMC and obvious advantages on drug adsorption and in vivo distribution, and exerted stronger anti-inflammatory effect after making specific response to the in vivo chiral environment.

Recent Research Progress of Chiral Small Molecular Antitumor-Targeted Drugs Approved by the FDA From 2011 to 2019.

Chiral drugs usually contain chiral centers, which are present as single enantiomers or racemates. Compared with achiral drugs, they have significant advantages in safety and efficacy with high stereoselectivity. Of these drugs, chirality not only exerts influence on the solubility and pharmacokinetic characteristics but also has specific mechanistic characteristics on their targets. We noted that small molecules with unique chiral properties have emerged as novel components of antitumor drugs approved by the FDA in decade. Since approved, these drugs have been continuously explored for new indications, new mechanisms, and novel combinations. In this mini review, recent research progress of twenty-two FDA-approved chiral small molecular-targeted antitumor drugs from 2011 to 2019 is summarized with highlighting the potential and advantages of their applications. We believe that these updated achievements may provide theoretical foundation and stimulate research interests for optimizing drug efficacy, expanding clinical application, overcoming drug resistance, and advancing safety in future clinical administrations of these chiral targeted drugs.

Structural Basis of the Modulation of the Voltage‐Gated Calcium Ion Channel Cav1.1 by Dihydropyridine Compounds**

Abstract1,4‐Dihydropyridines (DHP), the most commonly used antihypertensives, function by inhibiting the L‐type voltage‐gated Ca2+ (Cav) channels. DHP compounds exhibit chirality‐specific antagonistic or agonistic effects. The structure of rabbit Cav1.1 bound to an achiral drug nifedipine reveals the general binding mode for DHP drugs, but the molecular basis for chiral specificity remained elusive. Herein, we report five cryo‐EM structures of nanodisc‐embedded Cav1.1 in the presence of the bestselling drug amlodipine, a DHP antagonist (R)‐(+)‐Bay K8644, and a titration of its agonistic enantiomer (S)‐(−)‐Bay K8644 at resolutions of 2.9–3.4 Å. The amlodipine‐bound structure reveals the molecular basis for the high efficacy of the drug. All structures with the addition of the Bay K8644 enantiomers exhibit similar inactivated conformations, suggesting that (S)‐(−)‐Bay K8644, when acting as an agonist, is insufficient to lock the activated state of the channel for a prolonged duration.

Structural Basis of the Modulation of the Voltage-Gated Calcium Ion Channel Cav 1.1 by Dihydropyridine Compounds*.

1,4‐Dihydropyridines (DHP), the most commonly used antihypertensives, function by inhibiting the L‐type voltage‐gated Ca2+ (Cav) channels. DHP compounds exhibit chirality‐specific antagonistic or agonistic effects. The structure of rabbit Cav1.1 bound to an achiral drug nifedipine reveals the general binding mode for DHP drugs, but the molecular basis for chiral specificity remained elusive. Herein, we report five cryo‐EM structures of nanodisc‐embedded Cav1.1 in the presence of the bestselling drug amlodipine, a DHP antagonist (R)‐(+)‐Bay K8644, and a titration of its agonistic enantiomer (S)‐(−)‐Bay K8644 at resolutions of 2.9–3.4 Å. The amlodipine‐bound structure reveals the molecular basis for the high efficacy of the drug. All structures with the addition of the Bay K8644 enantiomers exhibit similar inactivated conformations, suggesting that (S)‐(−)‐Bay K8644, when acting as an agonist, is insufficient to lock the activated state of the channel for a prolonged duration.

Design of chiral mesoporous silica nanorods using ursodeoxycholic acid/chenodeoxycholic acid and CTAB as templates for chiral-selective release of achiral drugs

Twisted rod-like structured chiral mesoporous silicas (CMSs) have been firstly synthesized with the novel template systems from ursodeoxycholic acid (UDCA)/chenodeoxycholic acid (CDCA) and CTAB. CMSs were characterized by various instrumental techniques, demonstrating highly ordered hexagonal mesoscopic phase and twisted rod-like morphology. Induced circular dichroism (ICD) indicated the preferential optical activity of the CMSs with involving phenol as a probe. Besides, CMSs exhibited chiral-selective delivery of achiral drug indometacin (IMC) and nimesulide (NMS) in simulated chiral environment. We believe that the novel synthesized CMSs were expected to be desirable carriers for drug delivery in the pharmaceutical field to extend the applications of inorganic nanomaterials.

Chiral Mesoporous Silica Materials: A Review on Synthetic Strategies and Applications.

Because of its tunable textural properties and chirality feature, chiral mesoporous silica (CMS) gained significant consideration in many fields and has been developed rapidly in recent years. In this review, we provide an overview of synthesis strategies for fabricating CMS together with its main applications. The properties of CMS, including morphology and mesostructures and enantiomer excess (ee), can be altered according to the synthetic conditions during the synthesis process. Despite its primary stage, CMS has attracted extensive attention in many fields. In particular, CMS nanoparticles are widely used for enantioselective resolution and adsorption of chiral compounds with desirable separation capability. Also, CMS acts as a promising candidate for the effective delivery of chiral or achiral drugs to produce a chiral-responsive manner. Moreover, CMS also plays an important role in chromatographic separations and asymmetric catalysis. There has been an in-depth review of the synthetic methods and mechanisms of CMS. And this review aims to give a deep insight into the synthesis and application of CMS, especially in recent years, and highlights the significance that it may have in the future.

Ruthenium-Catalyzed Asymmetric Allylic Alkylation of Isatins.

A new ruthenium-based catalytic system for branched-selective asymmetric allylic alkylation is disclosed and applied to the synthesis of chiral isatin derivatives. The catalyst, which is generated in situ from commercially available CpRu(MeCN)3PF6 and a BINOL-derived phosphoramidite, is both highly active (TON up to 180) and insensitive to air and moisture. Additionally, the N-alkylated isatins accessible using this methodology are versatile building blocks that are readily transformed into chiral analogs of achiral drug molecules.

The On-Off chiral mesoporous silica nanoparticles for delivering achiral drug in chiral environment.

In the current stage, the On-Off mechanism of chiral mesoporous silica nanoparticles (CMSN) for delivering achiral drug in chiral environment has rarely been reported. Herein, On-Off chiral mesoporous silica nanoparticles (On-Off-D-CMSN and On-Off-L-CMSN) were successfully synthesized and its particular contribution in delivering achiral drug indometacin (IMC) in chiral environment was mainly studied. The as-synthesized On-Off-D-CMSN and On-Off-L-CMSN were verified by fourier transform infrared spectrometer and circular dichroism. The transmission electron microscope test and nitrogen adsorption/desorption analysis showed that On-Off-D-CMSN and On-Off-L-CMSN were regular spheres with concealed pore channels. The zeta potential analysis demonstrated that the grafting functional groups distributed on the inner and outer surfaces of On-Off-D-CMSN and On-Off-L-CMSN. Through dissolution experiment, the drug release of IMC loaded On-Off-D-CMSN (84%) and IMC loaded On-Off-L-CMSN (70%) were about 2.4 and 2.0 times higher than pure IMC (35%) in pH 6.8 phosphate buffer solution (PBS), respectively. IMC loaded On-Off-D-CMSN and IMC loaded On-Off-L-CMSN exerted different chiral recognition functions with On-Off mechanism in in-vitro chiral environment (pH 6.8 PBS-L and pH 6.8 PBS-D). The results of anti-inflammation pharmacodynamics further demonstrated that On-Off-D-CMSN and On-Off-L-CMSN can trigger chiral biological environment to achieve on or off chiral recognition functions. The unique advantages of On-Off chiral mesoporous silica nanoparticles in triggering chiral biological environment can provide valuable instruction for designing drug delivery system.

Ultrafast Chiral Chromatography as the Second Dimension in Two-Dimensional Liquid Chromatography Experiments.

Chromatographic separation and analysis of complex mixtures of closely related species is one of the most challenging tasks in modern pharmaceutical analysis. In recent years, two-dimensional liquid chromatography (2D-LC) has become a valuable tool for improving peak capacity and selectivity. However, the relatively slow speed of chiral separations has limited the use of chiral stationary phases (CSPs) as the second dimension in 2D-LC, especially in the comprehensive mode. Realizing that the recent revolution in the field of ultrafast enantioselective chromatography could now provide significantly faster separations, we herein report an investigation into the use of ultrafast chiral chromatography as a second dimension for 2D chromatographic separations. In this study, excellent selectivity, peak shape, and repeatability were achieved by combining achiral and chiral narrow-bore columns (2.1 mm × 100 mm and 2.1 mm × 150 mm, sub-2 and 3 μm) in the first dimension with 4.6 mm × 30 mm and 4.6 mm × 50 mm columns packed with highly efficient chiral selectors (sub-2 μm fully porous and 2.7 μm fused-core particles) in the second dimension, together with the use of 0.1% phosphoric acid/acetonitrile eluents in both dimensions. Multiple achiral × chiral and chiral × chiral 2D-LC examples (single and multiple heart-cutting, high-resolution sampling, and comprehensive) using ultrafast chiral chromatography in the second dimension are successfully applied to the separation and analysis of complex mixtures of closely related pharmaceuticals and synthetic intermediates, including chiral and achiral drugs and metabolites, constitutional isomers, stereoisomers, and organohalogenated species.

Investigation of the effect of mobile phase composition on selectivity using a solvent-triangle based approach in achiral SFC

Defining a method development methodology for achiral drug impurity profiling in SFC requires a number of steps. Initially, diverse stationary phases are characterized and a small number of orthogonal or dissimilar phases are selected for further method development. In this paper, we focus on a next step which is the investigation of the modifier composition on chromatographic selectivity. A solvent-triangle based approach is used in which blends of organic solvents, mainly ethanol (EtOH), propanol (PrOH), acetonitrile (ACN) and tetrahydrofuran (THF) mixed with methanol (MeOH) are tested as modifiers on six dissimilar stationary phases. The tested modifier blends were composed to have equal eluotropic strengths as calculated on bare silica. The modifier leads to minor changes in terms of elution order, retention and mixture resolution. However, varying only the modifier composition on a given stationary phase does not lead to the creation of dissimilar systems. Therefore the modifier composition is an optimization parameter, with the stationary phase being the factor determining most the selectivity of a given mixture in achiral SFC.

Racemic drug resolution: a comprehensive guide

The human body is amazingly chirally selective, and consequently enantiopure drugs are essential for treating disease. Nowadays, market approval of enantiopure drugs has increased exponentially whereas it has tremendously decreased for racemic and achiral drugs.

Prostereoisomerism and biological activity: possible implications for drug design

Prostereoisomerism (PIM), representing a subgroup within the achiral class of molecules, is manifested in a chiral environment. Although this is regardless of the orientation of the prostereoisomeric (PIC) molecule, PIM is manifested most emphatically in relation to a chiral surface (`two-dimensional chirality'). Then PIM is tantamount to `de facto chirality' as attachment of the PIC molecule to the surface leads to diastereomeric possibilities (cf. Ogston's hypothesis). Furthermore, the formation of host--guest complexes requires a steric complementarity between the component molecules. The fact that the weak dispersive forces involved therein require an optimum distance implies a `snugness of fit' criterion. This further implies that a chiral host prefers a chiral guest molecule, and a chiral surface prefers a PIC molecule as substrate. These indicate a general stereochemical criterion for host--guest complexation that is particularly relevant to the case of biological receptors. Indeed, a survey of several known achiral drug molecules indicates that they generally possess at least one PIC moiety, lending credence to the above arguments. Thus, it would appear that PIM represents a maximum level of molecular symmetry for biological activity to be manifested efficiently.

Separation performance of vancomycin-bonded stationary phase

Vancomycin is one of the macrocyclic antibiotics with complex molecular structure. Based on the various functional groups of vancomycin, a vancomycin-bonded stationary phase using glutaraldehyde as the spacer was prepared. Its chromatographic properties in reversed-phase, ion exchange and hydrophilic phase modes were investigated separately. The prepared stationary phase showed the typical characteristic of the reversed-phase stationary, when the organic solvent content was low in the mobile phase. On the contrary, its chromatographic characteristic transformed into hydrophilic phase mode with the organic solvent content increased in the mobile phase. Owing to the amino groups of vancomycin, ion exchange mode can also be applied to the separation method development. The vancomycin-bonded stationary phase was applied to the separation of eight achiral drugs and stevioside in reversed-phase, ion exchange and hydrophilic phase modes. The separations were achieved in three different kinds of separation modes by using appropriate chromatographic conditions. The results provide guidance for the design of new types of stationary phase, and method development of chromatographic stationary phases modified by special compounds with complex construction in corresponding separation modes.

Analytical Method Development and Validation of Pharmaceutical Analysis Using Chromatographic Techniques

Analytical methods including chromatographic methods are commonly used for the quantitative and qualitative analysis of raw materials, drug substances, drug products, and compounds in biological samples in pharmaceutical industry. The components monitored include chiral or achiral drugs, process impurities, residual solvents, excipients such as preservatives, degradation products, extractable and leachable from container and closure or manufacturing process, pesticide in drug product from plant origin, and metabolites. Validation of an analytical method which is used during drug development and drug manufacturing is required to demonstrate that the methods are fit for their intended purpose. Additionally, the pharmaceutical industry around the world is subject to extensive regulations due to the nature of its products. Analytical chemists play important roles in monitoring the drugs in their dosage forms and biological samples. From the viewpoints mentioned above, the title of this special issue was chosen so as to ask chemists to appreciate their great roles in chemistry science. This special issue features 8research articles. In this special issue, development of chromatographic methods such as high performance liquid chromatography, gas chromatography, micellar liquid chromatography, and their validations is presented. The purpose of this special issue will be to serve as a guide to what chromatographic methods bring to analytical and medicinal chemistry and other pharmaceutical sciences as well as briefly review their role in drugs and the new developments and validation of assay methods of pharmaceutically active compounds. Also, recent developments of application, evaluation, and validation of chromatographic methods are focused on by key topics in drug developments and analysis by assessment of the distinguished authors of this special issue. We hope that the reader will find a number of topics of interest and that additional new ideas will emerge from this special issue.