Enantioselective separation and determination of ibuprofen: Stereoselective pharmacokinetics, pharmacodynamics and analytical methods.

Ibuprofen (IBP), the 29th most prescribed drug in the United States in 2019, is a widely used nonsteroidal anti-inflammatory drug (NSAID) comprising two enantiomers, (R)-IBP and (S)-IBP, collectively known as (RS)-IBP. This critical review examines analytical techniques for the enantioselective separation and determination of IBP enantiomers, crucial for pharmaceutical and clinical applications. The review focuses on state-of-the-art methods, including chromatographic techniques including high-performance liquid chromatography, gas chromatography, liquid chromatography-tandem mass spectrometry, and some other techniques. This review addresses pharmacokinetics, pharmacology, and side effects of each enantiomer, ensuring safe drug usage. By consolidating diverse analytical methods and their applicability in different matrices, this review serves as a valuable resource for researchers, analysts, and practitioners in pharmaceutical analysis, pharmacology, and clinical studies.

Stereoselective analysis of chiral pesticides: a review.

Chiral organic pollutants, including pesticides, herbicides, medicines, flame retardants, and polycyclic musk, represent a significant threat to both the environment and human health. The presence of asymmetric centers in the structure of chiral pesticides introduces stereoisomers with distinct distributions, fates, biomagnification capacities, and cytotoxicities. In aquatic environments, pesticides, as persistent/pseudo-persistent compounds, have been detected in substantial quantities, posing severe risks to non-target species and, ultimately, public health through water supply and food exposures. In response to this environmental challenge, stereoselective analytical methods have gained prominence for the identification of pesticide/drug enantiomers in recent years. This review examines the environmental impact of chiral pesticides, emphasizing the distinct biological activities and distribution patterns of their stereoisomers. By highlighting the advancements in liquid chromatography for enantiomeric analysis, the review aims to underscore the urgent need for a comprehensive understanding of these pollutants to facilitate informed remediation strategies and ensure the safer dispersal of chiral organic pollutants in the environment, thereby addressing the potential risks they pose to ecosystems and human health. Future research should focus on developing sustainable and efficient methodologies for the precise analysis of stereoisomers in complex matrices, particularly in sewage water, emphasizing the importance of sewage processing plants in ensuring water quality.

Recent advances in the antioxidant activity of metal-curcumin complexes: a combined computational and experimental review.

Curcumin, an extensively studied phytochemical compound, has gained attention for its potential therapeutic applications across a spectrum of diseases. Its notable attributes include its relatively high tolerability within the human body and its perceived absence of adverse side effects. This review article presents a comprehensive overview of the antioxidant effects exhibited by complexes formed by curcumin and curcumin derived ligands with metals like Mn, Cu, Fe, Zn, Ga and In, which leads to toxic effects beyond a certain limit, based on both experimental and theoretical findings. Additionally, the discussion delves into metal-curcumin complexes characterized by stoichiometries of 1:1 and 1:2, exploring their geometric arrangements and corresponding antioxidant activity, as highlighted in recent studies. These complexes hold the promise of improving curcumin's solubility, stability, and bioavailability, potentially augmenting its overall therapeutic potential and expanding its scope for medical applications.

Computational insight of antioxidant and doxorubicin combination for effective cancer therapy.

Doxorubicin (DOX) is the most effective antineoplastic agent, destroys cancer cells by interrupting cellular function. However, the serious side effects on the heart limits its utility. To curb these unwanted side effects, nutritionist recommend antioxidants use along with DOX while chemotherapy. But it was not supported by various oncologists as it can alter the toxicity of DOX towards cancer cells. Therefore, here we explored the in silico pharmacokinetics and combination effect of DOX and antioxidants on topoisomerases-II (Top-II) and cyclophilin D (Cyp-D) therapeutic targets involved in cancer proliferation and post-myocardial infarction, respectively. The molecular docking study was conducted on target proteins and DOX including most prescribed antioxidants (melatonin, N-acetylcysteine (NAC), glutathione (GSH), ß-carotene and vitamin C). GSH showed effective binding potential for Top-II and Cyp-D active sites, but other considered antioxidants possess low binding affinity. The highest docked conformations were subjected to molecular dynamics (MD) simulations to understand conformer stability of DOX and GSH with Cyp-D and Top-II for 100 ns. The results revealed that ligands pose at Top-II active sites where DOX showed strong binding affinity to DNA binding pocket and GSH to a buried site. The computational data summarised and proposed the GSH and DOX combination as antagonist effects on Top-II. Conversely, the binding compactness of GSH improved due to surface fit at the active pocket of Cyp-D and completely blocking DOX binding affinity, suppress adverse reactions of post-myocardial infarction.Communicated by Ramaswamy H. Sarma.

Free radical scavenging activity of gallic acid toward various reactive oxygen, nitrogen, and sulfur species: a DFT approach.

Gallic acid is a well-recognized naturally occurring compound possessing antioxidant activities. The free radical scavenging ability of gallic acid for fifty reactive species, such as oxygen, nitrogen, and sulfur-containing species, has been studied using the formal hydrogen atom transfer mechanism. The theoretical studies have been conducted in the gas phase and aqueous solution at M05-2X/6-311++G** level using the density functional theory (DFT) calculations. The relative damaging potential of all the reactive species has been compared by investigating their hydrogen atom and electron affinity. Furthermore, a comparison of their relative reactivity was made by evaluating several global chemical reactivity descriptors. Additionally, the feasibility of scavenging the species by gallic acid has been studied by computing the redox potentials and equilibrium constants for the overall process in the aqueous solution.

Recent advances in the antioxidant activity and mechanisms of chalcone derivatives: a computational review.

In this review, we have reported the antioxidant mechanisms and structure-antioxidant activity relationship of several chalcone derivatives, investigated in the recent past, based on the density functional theory (DFT) calculations, considering free radical scavenging and metal chelation ability. The antioxidant mechanisms include hydrogen atom transfer (HAT), sequential proton loss electron transfer (SPLET), single electron transfer followed by proton transfer (SET-PT), sequential proton loss hydrogen atom transfer (SPLHAT), sequential double proton loss electron transfer (SdPLET), sequential triple proton loss double electron transfer (StPLdET), sequential triple proton loss triple electron transfer (StPLtET), double HAT, double SPLET, double SET-PT, triple HAT, triple SET-PT, triple SPLET, proton-coupled electron transfer (PCET), single electron transfer (SET), radical adduct formation (RAF) and radical adduct formation followed by hydrogen atom abstraction (RAF-HAA). Furthermore, solvent effects have also been considered using different solvation models. The feasibility of scavenging different reactive oxygen and nitrogen species (ROS/RNS) has been discussed considering various factors such as the number and position of hydroxyl as well as methoxy groups present in the antioxidant molecule, stability of the species formed after scavenging reactive species, nature of substituent, steric effects, etc. This review opens new perspectives for designing new compounds with better antioxidant potential.

Enantioseparation of linezolid and tedizolid using validated high-performance liquid chromatographic method.

This paper reports the separation of two chiral antibacterial agents namely, linezolid and tedizolid using a validated high-performance liquid chromatographic method. In the current work, glycopeptide-based chiral column, CHIROBIOTIC® V2 (5-µm particle size, L × I.D. 25 cm × 4.6 mm) was employed with a mobile phase containing methanol and 0.15% aq. trifluoracetic acid (75:25%, v/v) in isocratic elution approach at flow rate of 1 ml min-1 . The separation condition was customized (in terms of resolution values and retention times) was carried out by changing the content of the mobile phase, column temperature, flow rate, and so on. Results showed that the chromatographic separation was achieved within 15 min and average resolution values were 4.6 and 4.8 for tedizolid and linezolid, respectively. The detection limit values were 14.85 and 14.16 ng ml-1 , respectively, for tedizolid enantiomers. Further, validation of separation parameters was performed by considering the international conference on harmonization guidelines, and ultimately, the mechanism of chiral recognition was also established.

Detection and remediation of chiral pharmaceuticals from wastewater: A review.

Chiral organic pollutants including pharmaceuticals, pesticides, herbicides, flame retardants, and polycyclic musk cause significant risks to both the environment and human health. Chiral pharmaceuticals (CPs) are among the significant class of pseudo-persistent substances that have been observed in the concentration level from nanomolar to micromolar quantities and cause bad impacts on nontargeted species and direct or indirect human health issues due to water and foodborne contamination. The CPs may contain one or more chiral centers in their structural framework and thus enantiomers of CPs often possess different distribution, fate, bioaccumulation potential, and toxicity. The enantioselective chromatographic techniques have been extensively applied to detect drug enantiomers during the last few years. Bioremediation techniques offer unique characteristics above conventional remediation procedures as these could be cost-effective and accomplish total organic pollutant decomposition without causing collateral damage to the site material or native flora and fauna. This review describes the impacts of chiral pharmaceuticals on the environment; detection technologies (particularly liquid chromatography), and important remedial measures for safer disposal of such pollutants.

Chirality of antidepressive drugs: an overview of stereoselectivity.

Stereochemistry plays an important role in drug design because the enantiomers of a drug frequently vary in their biological action and pharmacokinetic profiles. Racemates of a drug with either an inactive or an unsafe enantiomer can lead to detrimental effects. The manufacturing industry may still produce racemates, but such decisions must pass through rigorous analyses of the pharmacological and pharmacokinetic characteristics of the particular enantiomer related to the racemates. The pharmacokinetics of antidepressants or antidepressive agents is stereoselective and predominantly favors one enantiomer. The use of pure enantiomers offers (i) better specificity than the racemates in terms of certain pharmacological actions, (ii) enhanced clinical indications, and (iii) optimized pharmacokinetics. Therefore, controlling the stereoselectivity in the pharmacokinetics of antidepressive drugs is of critical importance in dealing with depression and psychiatric conditions. The objective of this review is to highlight the importance of the stereochemistry of antidepressants in the context of the design and development of new chirally pure pharmaceuticals, the potential complications caused by using racemates, and the benefits of using pure enantiomers.

Stereochemical facets of clinical ß-blockers: An overview.

The modern ß-adrenergic agonists (ß-blockers) possess one or more than one chiral center in their structure. Two enantiomers exhibit distinct pharmacodynamic and pharmacokinetic behaviors. Current progress in drug designing has resulted in the ability to understand the role of chirality in modern therapeutics. Furthermore, with a greater understanding of the molecular structure of precise drug targets, development of new drugs is directed towards the pure enantiomers instead of its racemates. The present review deals with a discussion on the stereochemical facets of chiral clinical ß-blockers. This review provides details of stereo-selectivity in the pharmacological behavior of some of ß-blockers and their metabolites. An effort has been made on highlighting the distinction between the therapeutic behavior of the racemic mixtures and pure enantiomers.

Sensitive enantioseparation and determination of isoprenaline in human plasma and pharmaceutical formulations.

A simple, sensitive and fast RPHPLC method was developed and validated for the enantioselective determination of (RS)-isoprenaline (Ipn) in human plasma. The enantiomers were converted to diastereomeric derivatives using s-triazine (cyanuric chloride) based chiral derivatizing reagents. l-isoleucine and l-methionine were introduced as chiral auxiliary in s-triazine and two new monochloro-s-triazine reagents were synthesized. These reagents were characterized and used for synthesis of diastereomeric derivatives of (RS)-Ipn spiked in human plasma. (RS)-Ipn was isolated (purified and characterized) from a commercial pharmaceutical formulation and was used as the standard racemic sample. Structures of the two diastereomeric derivatives were optimized for lowest energy using the Gaussian 09 Rev A. 02 program and hybrid density functional B3LYP with 6-31G* basis set which showed the spatial orientation of hydrophobic groups on stereogenic centers in the diastereomeric derivatives. The results were correlated with the mechanism of separation and elution order. Limit of detection values were found to be 24.6 and 26.8 ng mL-1 for the first and second eluting diastereomeric derivatives, respectively.

Design and synthesis of CoIIHMTAA-14/16 macrocycles and their nano-composites for oxygen reduction electrocatalysis.

The major concerns in the design of macrocycle based-ORR catalysts are: (i) understanding the macrocyclic, π-conjugation, central metal and substituent effects on ORR electrocatalysis; and (ii) the use of macrocycles on the electrode surface for the retention of ORR activity because of their poor stability. In this work, we demonstrated the aromaticity/π-electron conjugation effect on ORR activity by using the same macrocycles [HMTAA-14 and 16 (hexamethyltetraaza [14] and [16] annulenes)] with a difference in their macrocyclic cavity/π-electron conjugation. The macrocycles CoIIHMTAA-14 and CoIIHMTAA-16 and their nanocomposites with highly conductive carbon black were prepared by a microwave-assisted method and characterized by using multiple spectroscopy techniques. Comparative redox and oxygen reduction activity studies of CoIIHMTAA-14 and CoIIHMTAA-16 were undertaken by using cyclic voltammetry and linear sweep voltammetry in an alkaline medium. The composite CoIIHMTAA-16@C showed good ORR activity compared to CoIIHMTAA-14@C in O2-saturated KOH electrolyte. Since the CoIIHMTAA-14 and CoIIHMTAA-16 systems have a similar central atom and substituents, the shift of the ORR peak position in the +ive potential region for HMTAA-16 can be attributed to the difference in the size of the macrocyclic cavity (macrocyclic effect) and the extra stability of HMTAA-16 annulene due to its aromaticity.

Electrochemical studies of DNA interaction and antimicrobial activities of MnII, FeIII, CoII and NiII Schiff base tetraazamacrocyclic complexes.

Tetraazamacrocyclic complexes of MnII, FeIII, CoII and NiII have been synthesized by template method. These tetraazamacrocycles have been analyzed with various techniques like molar conductance, IR, UV-vis, mass spectral and cyclic voltammetric studies. On the basis of all these studies, octahedral geometry has been assigned to these tetraazamacrocyclic complexes. The DNA binding properties of these macrocyclic complexes have been investigated by electronic absorption spectra, fluorescence spectra, cyclic voltammetric and differential pulse voltammetric studies. The cyclic voltammetric data showed that ipc and ipa were effectively decreased in the presence of calf thymus DNA, which is a strong evidence for the interaction of these macrocyclic complexes with the calf thymus DNA (ct-DNA). The heterogeneous electron transfer rate constant found in the order: KCoII>KNiII>KMnII which indicates that CoII macrocyclic complex has formed a strong intercalated intermediate. The Stern-Volmer quenching constant (KSV) and voltammetric binding constant were found in the order KSV(CoII)>KSV(NiII)>KSV(MnII) and K+(CoII)>K+(NiII)>K+(MnII) which shows that CoII macrocyclic complex exhibits the high interaction affinity towards ct-DNA by the intercalation binding. Biological studies of the macrocyclic complexes compared with the standard drug like Gentamycin, have shown antibacterial activities against E. coli, P. aeruginosa, B. cereus, S. aureus and antifungal activity against C. albicans.

Bioanalysis and enantioseparation of dl-carnitine in human plasma by the derivatization approach.

BACKGROUND: L-carnitine is an over the counter drug, used to treat disorders like cardiomyopathy, skeletal myopathy, hypoglycemia and hyperammonemia. Preparations containing D-carnitine should be avoided by dialysis patients because it has toxic influence on biochemical processes by inhibiting the carnitine acetyltransferase. Therefore, it is of utmost importance to assess and control the content of D-carnitine. METHODS: A HPLC method was developed and validated for determination and enantiomeric resolution of DL-carnitine in human plasma by derivatization approach. (S)-Naproxen-based three derivatizing reagents were synthesized and applied. CONCLUSION: The limit of detection values were found to be 1.26 and 1.35 ng ml(-1) for the two isomers. The method is simple, reproducible, and can be used for routine analysis in laboratories for control of enantiomeric purity of carnitine.

Preparative enantioseparation of (RS)-baclofen: determination of molecular dissymmetry.

The present work reports preparative enantioseparation of (RS)-baclofen using thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC). Diastereomers were synthesized using a new monochloro-s-triazine-based chiral derivatizing reagent (CDR), namely, N-(4-chloro-6-piperidinyl-[1,3,5]-triazine-2-yl)-L-phenylalanine, under microwave irradiation. Acetonitrile-0.1% aq. triflouroacetic acid in gradient elution mode and CH3 OH-CH2 Cl2 (4:5; v/v) were successful as mobile phase in HPLC and TLC, respectively. The two diastereomers were isolated by preparative TLC. Molecular dissymmetry was established by developing the lowest energy optimized structures of the diastereomers based on Density Functional Theory and with the help of (1) H NMR showing anisotropic effect associated with aromatic ring of s-triazine (in the CDR). The configuration of diastereomers was established as [L-Phe-(R)-Bac] and [L-Phe-(S)-Bac], where the first notation refers to the configuration of chiral auxiliary (of the CDR) and the second to that of the analyte Bac. Limits of detection were found to be 0.056 and 0.061 ng mL(-1), respectively, for the two diastereomers. Determination of absolute configuration of the two diastereomers lent support to the elution order and separation mechanism.

Synthesis of variants of Marfey's reagent having d-amino acids as chiral auxiliaries and liquid-chromatographic enantioseparation of (RS)-Mexiletine in spiked plasma: assessment and comparison with L-amino acid analogs.

Five d-amino acids have been used for the first time to synthesize chiral derivatizing reagents (as variants of Marfey's reagent) by nucleophilic displacement of one of the fluorine atoms in 1,5-difluoro-2,4-dinitrobenzene as against the literature reports on application of only l-amino acids or their amides as chiral auxiliaries in dinitrobenzene (DNB) moiety. Five other DNB based reagents were also prepared by nucleophilic substitution of fluorine atom with the set of the same amino acids in l-configuration, as chiral auxiliaries. These reagents were characterized and used for synthesis of diastereomers of (RS)-Mexiletine spiked in human plasma. Diastereomers were synthesized employing microwave irradiation and were separated on reversed-phase C18 column. Performance of the two types of chiral derivatizing reagents was compared. The reagents containing d-amino acids provided enhanced separation of diastereomers than those containing l-amino acids. The best resolution was obtained using mobile phase consisting of acetonitrile and 0.1% trifluoroacetic acid in gradient mode. The detection was carried out at 340nm. The method so developed was validated for linearity, accuracy and precision. The limit of quantitation was found to be approximately 25.2ngmL(-1) in human plasma.