Cinchona Research Articles

Enantiospecific Analysis of Carboxylic Acids Using Cinchona Alkaloid Dimers as Chiral Solvating Agents.

Cinchona alkaloid derivatives as Brønsted base catalysts have attracted considerable attention in the field of asymmetric catalysis. However, their potential application as chiral solvating agents has not been described. In this research, we investigated the use of the Cinchona alkaloid dimer, namely, (DHQ)2PHAL, as a chiral solvating agent for discerning various mandelic acid derivatives through 1H NMR spectroscopy. The addition of catalytic amounts of DMAP facilitated this process. Our experimental results demonstrate that dimeric (DHQ)2PHAL exhibits remarkable chiral discrimination properties regarding the diagnostic split protons of 1H NMR signals (including 24 examples, up to 0.321 ppm). Furthermore, it serves as an excellent chiral discriminating agent and provides good resolution for racemic chiral phosphoric acid as determined by 31P NMR spectroscopy. The quality of enantiodifferentiation has also been evaluated by means of the parameter "resolution (Rs)". Significantly, this class of CSAs based on (alkaloid)2linker systems with an azaaromatic linker can be directly employed, which is commercially available in an enantiopure form at very low cost and exhibits promising potential in determining the enantiopurity of α-hydroxy acids by chemoselective and biocatalytic reactions.

Organocatalytic Asymmetric Conjugate Addition of Fluorooxindoles to Quinone Methides.

Fluorooxindoles undergo asymmetric Michael addition to para-quinone methides under phase-transfer conditions with 10 mol% of a readily available cinchona alkaloid ammonium catalyst. This reaction affords sterically encumbered, multifunctional fluorinated organic compounds displaying two adjacent chirality centers with high yields, ee's and dr's.

The Role of Aromatic Alcohol Additives on Asymmetric Organocatalysis Reactions: Insights from Theory.

The presence of an aromatic additive has been seen to enhance, often significantly, the enantioselectivity and yield in asymmetric organocatalysis. Considering their success across a dizzying range of organocatalysts and organic transformations, it would seem unlikely that a common principle exists for their functioning. However, the current investigations with DFT suggest a general principle: the phenolic additive sandwiches itself, through hydrogen bonding and π⋅⋅⋅π stacking, between the organocatalyst coordinated electrophile and nucleophile. This is seen for a wide range of experimentally reported systems. That such complex formation leads to enhanced stereoselectivity is then demonstrated for two cases: the cinchona alkaloid complex (BzCPD), catalysing thiocyanation (2-naphthol additive employed), as well as for L-pipecolicacid catalysing the asymmetric nitroaldol reaction with a range of nitro-substituted phenol additives. These findings, indicating that dual catalysis takes place when phenolic additives are employed, are likely to have a significant impact on the field of asymmetric organocatalysis.

Cinchonine: A Versatile Pharmacological Agent Derived from Natural Cinchona Alkaloids.

Cinchonine is one of the Cinchona alkaloids that is commercially extracted from the Peruvian bark of Cinchona officinalis L. (Family: Rubiaceae). It is also obtained in much lower quantities from other species of Cinchona, such as Cinchona calisaya, Cinchona succirubra, and Cinchona pubescens, and in some other plants, such as Remijia peruviana. Cinchonine has been historically used as an anti-malarial agent. It also has a wide range of other biological properties, including anti-cancer, anti-obesity, anti-inflammatory, anti-parasitic, antimicrobial, anti-platelet aggregation, and anti-osteoclast differentiation. This review discusses the pharmacological activity of cinchonine under different experimental conditions, including in silico, in vitro, and in vivo. It also covers the compound's physicochemical properties, toxicological aspects, and pharmacokinetics. A comprehensive literature search was conducted on multiple online databases, such as PubMed, Scopus, and Google Scholar. The aim was to retrieve a wide range of review/research papers and bibliographic sources. The process involved applying exclusion and inclusion criteria to ensure the selection of relevant and high-quality papers. Cinchonine has numerous pharmacological properties, making it a promising compound for various therapeutic applications. It induces anti-cancer activity by activating caspase-3 and PARP-1, and triggers the endoplasmic reticulum stress response. It up-regulates GRP78 and promotes the phosphorylation of PERK and ETIF-2α. Cinchonine also inhibits osteoclastogenesis, inhibiting TAK1 activation and suppressing NFATc1 expression by regulating AP-1 and NF-κB. Its potential anti-inflammatory effects reduce the impact of high-fat diets, making it suitable for targeting obesity-related diseases. However, research on cinchonine is limited, and further studies are needed to fully understand its therapeutic potential. Further investigation is needed to ensure its safety and efficacy in clinical applications. Overall, this review article explains the pharmacological activity of cinchonine, its synthesis, and physicochemical properties, toxicological aspects, and pharmacokinetics.

Chiral zwitterionic stationary phases based on Cinchona alkaloids and dipeptides – design, synthesis and application in chiral separation

Chiral resolution of polar organic compounds such as amino acids and peptides represents an important chromatographic task due to increasing significance of natural species, which play important signaling and regulatory roles in the living organisms. Despite the number of available chiral stationary phases, this task remains challenging, since not many of the commercially available systems are capable to resolve non-derivatized zwitterionic species. In this study, we present a target-oriented design of a new class of chiral selectors. Pursuing the goal to separate amino acids, and especially short peptides, we have combined Cinchona alkaloids – quinine and quinidine – with three different biogenic dipeptides. We have synthesized six different chiral stationary phases, with selector loading of ∼200 μmol g−1, and tested their chiral recognition capabilities for acidic, basic and zwitterionic analytes using various mobile phases. We have observed that all chiral stationary phases retain the chiral anion exchange capability known for commercially available Cinchona-based columns leading to baseline or partial resolution of six out of ten analytes. The performance in chiral resolution of basic analytes is not optimum due to the weak cation exchange character of the peptidic residue. However, we report on encouraging results in the chiral resolution of short peptides, for which, depending on their structure, we see the chiral resolution of up to three stereoisomers (from four possible) in a preliminary screening.

Organocatalytic Stereoselective Decarboxylative Addition of α‐Amido Malonic Acid Half Oxyesters to Isatins

AbstractThe stereoselective reaction of α‐amido‐substituted malonic acid half oxyesters (α‐amido‐MAHOs) with isatins was developed. A cinchona alkaloid thiourea catalyst gave products bearing a tetrasubstituted stereogenic centre in high yields with high diastereo‐ and enantioselectivities (75–99% yield, 83:17–97:3 dr, 92:8–99:1 er). The obtained products can be converted into some chiral compounds without loss of enantiopurity. Density functional theory (DFT) calculations were conducted to clarify the origin of stereoselectivities, and suggested that the first stereogenic centre is set in the decarboxylation, the second in the protonation.

Asymmetric transfer hydrogenation of 2,3-diphenylpropenoic acids over heterogeneous palladium catalysts modified by cinchona alkaloids

Asymmetric catalytic methods are among the convenient syntheses procedures of optically pure organic compounds, many of which are valuable pharmaceutical intermediates. Applying heterogeneous catalysts may contribute to their economic and environmentally benign synthesis. Among the easiest and often used methods of introducing chiral centres in molecules are the reduction of prochiral unsaturated compounds. Although, several heterogeneous catalytic systems are known in which in situ chirally-modified metals are used, such catalysts have never been applied in asymmetric transfer hydrogenations. Here we report the enantioselective transfer hydrogenations of (E)-2,3-diphenylpropenoic acids over supported palladium catalysts modified by dihydrocinchonidine carried out in ordinary laboratory glassware using easily available, cheap hydrogen donor, i.e. potassium formate. High conversions and good enantioselectivities were obtained in transfer hydrogenations of various acids substituted on phenyl rings. Results obtained with various acid derivatives and with few cinchona alkaloid modifiers indicated that the transfer hydrogenations occur through a similar surface intermediate as the enantioselective hydrogenations with molecular hydrogen. A deuterium tracer study showed low deuterium incorporation in the product possibly due to dissociation of formate and exchange with the surface mobile hydrogens, however, these processes are strongly influenced by the donor cation. The asymmetric transfer hydrogenation may be carried out at over 2 g scale, thus may be used as an advantageous laboratory synthetic procedure without applying special precautions characteristic of gaseous reactants.

Impact of light conditions on the early development of Cinchona officinalis

Cinchona officinalis, a native plant species known in Peru as the cinchona tree, has civic importance because it represents the plant wealth of this nation and medicinal importance since it was for more than 300 years the only cure for malaria, and is currently threatened. The aim was to determine the effect of light conditions on the percentage of mortality, height increase, and diameter increase of Cinchona officinalis. In the community of La Cascarilla (5°39’48.87 “S 78°54’35.24 “W), two treatments were installed, forest massif (FM) and enrichment bands (EB). For each treatment, three replicates and 16 plants per replicate were used. Monthly evaluations were carried out in which the number of dead plants, plant height, and diameter were recorded. These parameters were correlated with precipitation, temperature, and photoperiod records of the study area. The results showed that mortality in FM was 27.1% higher than that reported in EB, while the increase in height and diameter increment in the FM plot was 45.5 and 25.1% higher than that obtained in EB. In addition, a negative correlation was observed between the percentage of mortality and precipitation (rs=-0.54), and between the increase in height and diameter increment with the maximum temperature (rs=-0.73 and rs=-0.60, respectively) for the FM treatment, while for the EB treatment, there was a negative correlation between the increase in height and precipitation (rs=-0.55) and a positive correlation between the diameter increment and the minimum temperature (rs=0.53). In general, shaded conditions allow a higher survival rate at the cost of reducing height and diameter increment.

Cinchona Alkaloid Polymers Demonstrate Highly Efficient Gene Delivery Dependent on Stereochemistry, Methoxy Substitution, and Length.

Nucleic acid delivery with cationic polymers is a promising alternative to expensive viral-based methods; however, it often suffers from a lower performance. Herein, we present a highly efficient delivery system based on cinchona alkaloid natural products copolymerized with 2-hydroxyethyl acrylate. Cinchona alkaloids are an attractive monomer class for gene delivery applications, given their ability to bind to DNA via both electrostatics and intercalation. To uncover the structure-activity profile of the system, four structurally similar cinchona alkaloids were incorporated into polymers: quinine, quinidine, cinchonine, and cinchonidine. These polymers differed in the chain length, the presence or absence of a pendant methoxy group, and stereochemistry, all of which were found to alter gene delivery performance and the ways in which the polymers overcome biological barriers to transfection. Longer polymers that contained the methoxy-bearing cinchona alkaloids (i.e., quinine and quinidine) were found to have the best performance. These polymers exhibited the tightest DNA binding, largest and most abundant DNA-polymer complexes, and best endosomal escape thanks to their increased buffering capacity and closest nuclear proximity of the payload. Overall, this work highlights the remarkable efficiency of polymer systems that incorporate cinchona alkaloid natural products while demonstrating the profound impact that small structural changes can have on overcoming biological hurdles associated with gene delivery.

Comparative Study of Cinchona Cinnamon Bark

Cinchona which belongs to family Rubiaceae, got its importance from the centuries because of its antimalarial activity. Alkaloids present in this herb, quinine, chichonine, quinidine and cinchonidine are the main, but percentage may vary in species to species. since the early 17 century, the sealkaloid are frequently used in Indian ayurvedic, siddha and traditional folk medicine to treating fever and still now in modern medicine cinchona alkaloids are used for the treatment of malaria as well as for other diseases and became the well-known drug after the treatment of malaria caused by Plasmodium Sp. Literature study revealed that along with the antimalarial activity the cinchona alkaloids has other potentially like anti-obesity, anticancer, anti-oxidant, anti-inflammatory , antimicrobial activity. Many herbal remedies have been employed in various medical systems for the treatment and management of different disease.Cinnamon is ever green tree of tropical area,a member of family Lauraceae, has been used in day to day routine as spice .Literature review on cinnamon releved that in mainly contain essential oil and important compounds like cinnamaldehyde, eugenol, cinnamic acid and cinnamon. It has got good anti-inflammatory, antioxidant, antimicrobial, antidiabetic, memory enhancer and many other Activities

Widened Scope of Drug Repurposing/Chiral Switches, Elements of Secondary Pharmaceuticals: The Quinine/Quinidine Case

Drug repurposing to new medical uses and chiral switches are elements of secondary pharmaceuticals. This article focuses on drug repurposing/chiral switches of the diastereomeric quasi-enantiomeric antimalarial quinine and antiarrhythmic quinidine, based on the histories of these drugs (1638–2022), applying a widened scope. Quinine, an essential medicine, changed the world. Drug repurposing is a strategy for identifying new uses for approved or investigational drugs outside the scope of the original medical indications. Potential drugs are not included in the definition of drug repurposing. Drug repurposing may be within or outside the therapeutic group, e.g., quinidine to quinine repurposing, from treatment of arrhythmia or severe malaria to uncomplicated malaria. The scope of chiral switches included racemate to single enantiomer and other switches of the status of chirality, e.g., racemate and quasi-racemate to scalemic mixtures. There are 16 quinine/quinidine stereoisomers. Given the multiple pharmacological activities of Cinchona alkaloid stereoisomers, this article calls for subjecting them to comprehensive drug repurposing/chiral switch searches for new medical uses.

Synthesis and Reactivity of Fluorinated Dithiocarboxylates to Prepare Thioamides-Effective Access to a 4-Styrenylthioamide-Cinchona Alkaloid Monomer.

A simple and rapid access to fluorinated dithioesters was developed by a one-pot sequence corresponding to a Grignard reaction-Mitsunobu type substitution. These activated dithioesters have shown excellent reactivity in an aminolysis reaction from simple or more complex primary amines such as cinchona alkaloids. A stoichiometric amount of amine was sufficient to prepare various thioamides, including a 4-styrenylthioamide cinchonidine monomer, under environmentally friendly conditions, at room temperature, and in a very short time.

Polymer-supported thioamide-derived cinchona alkaloids as efficient organocatalysts for the enantioselective decarboxylative protonation

A new family of copolymers based on styrene and a polymerizable cinchonidine thioamide derivative was synthesized by conventional radical polymerization. The copolymers were tested as homogeneous supported organocatalysts in the enantioselective decarboxylative protonation (EDP) of α-aminomalonate hemiesters giving access to α-amino acids under very mild conditions. These macromolecular catalysts could be prepared on a large scale and outperformed their unsupported analogues providing the desired products in high yield and enantioselectivity. Furthermore, recycling experiments were conducted which showed good enantioselectivities.

Cinchonine and cinchonidine alleviate cisplatin-induced ototoxicity by regulating PI3K-AKT signaling.

Cinchonine (CN) and its isomer cinchonidine (CD), two of the common cinchona alkaloids, are wildly used as antimalarial drugs. However, the effects of CN and CD on the auditory system are unknown. Molecular docking and molecular dynamics (MD) simulation were used for predicting effective drugs. The CCK-8 assay was conducted for assessing cell viability in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells. MitoSox Red staining revealed reactive oxygen species (ROS) amounts. TMRM staining was used to assess the mitochondrial membrane potential (ΔΨm). Immunofluorescence staining of myosin 7a was used to examine hair cells (HCs) in cisplatin-treated neonatal mouse cochlear explants, while TUJ-1 immunostaining was used for the detection of spiral ganglion neurons (SGNs). Cleaved caspase-3 and TUNEL immunostaining were utilized for apoptosis assessment. Immunoblot was carried out to detect PI3K-AKT signaling effectors. Pretreatment with CN or CD significantly increased cell viability and reduced mitochondrial dysfunction and ROS accumulation in cisplatin-treated HEI-OC1 cells. Immunofluorescent staining of cochlear explants showed that CN and CD attenuated cisplatin-induced damage to SGNs and HCs. Immunoblot revealed that CN and CD downregulated the expression of cleaved caspase-3 and activated PI3K-AKT signaling in cisplatin-injured HEI-OC1 cells. CD and CN can reduce ototoxicity caused by cisplatin and might help treat cisplatin-associated hearing loss.

Enantioselective Nucleophilic Vinylic Substitution (SNV) toward 3-Alkenyl-bisoxindoles Facilitated by C6' Steric Bulk of Cinchona Alkaloid.

A C6' bulky substituted quinine-catalyzed SNV reaction between 3-substituted oxindole and (E)-3-(nitromethylene)-oxindole was developed. This enantioselective C(sp3)-C(sp2) coupling furnished bisoxindole scaffolds featuring a vinyl-substituted all-carbon quaternary stereocenter with high stereoselectivities. In addition, the gram-scale synthesis and synthetic post-transformations were conducted to demonstrate the potential synthetic usefulness.

Chiral Modification of Ferrite Nanoparticles for Oxidative Kinetic Resolution of Benzoins

AbstractWe report the surface modification of ferrite nanoparticles (MFe2O4 NPs; M= Mn, Fe, Co, Ni, Cu, Zn) with chiral surfactants derived from cinchona alkaloids. The successful synthesis of chiral ferrites were characterized using powder X‐ray diffraction (PXRD), X‐ray photoelectron spectroscopy (XPS), Atomic force microscopy (AFM), Thermogravimetric analysis (TGA) and vibrating sample magnetometer (VSM). These chiral materials were highly active in the oxidative kinetic resolution (OKR) of racemic benzoins. Remarkably gemini surfactant modified Fe3O4 NPs were found to be a potential candidate in the OKR and (R)‐benzoin was isolated with 97% enantiomeric excess (ee). The sustainability of our catalyst has been demonstrated in the gram scale synthesis of (R)‐furoin (93% ee). The recyclability studies have also been performed and found that it could be recyclable with decrease in ee.

H22 Barking up the right tree: history of quinine

Abstract Quinine is considered to be one of the most important medical discoveries of the 17th century through its use in treating malaria. Since then, its applications have expanded, and quinine continues to be one of the most widely used drugs in dermatology. Quinine is found in the bark of the Cinchona tree found in the jungles of the Andean region of South America. The exact nature of its discovery remains unclear; however, there are tales of the Spanish Countess of Chinchon being cured of a recurring fever by using liquid containing Cinchona bark. This prompted her to return to Spain in 1638 with the seeds and precious bark; in 1742, botanist Carl Linnaeus named the tree Cinchona in her honour. During the early 17th century, the bark was ground into a powder and mixed with wine. In 1820, French scientists Pierre Pelletier and Joseph Caventou developed the processes to extract quinine from Cinchona bark, improving the potency of the medicine. In the 19th century, as the role of quinine in treating malaria spread, Europeans in the British colonies started planting Cinchona trees to avoid importing large amounts of the drug. Owing to its bitter taste, quinine was mixed with sugar and soda, creating the first tonic water. The tonic water was mixed with gin to make the bitterness of quinine more palatable. Winston Churchill claimed that this drink ‘saved more Englishmen’s lives, and minds, than all the doctors in the Empire’ (Simonetti O, Contini C, Martini M. The history of Gin and Tonic; the infectious disease specialist long drink. When gin and tonic was not ordered but prescribed. Infez Med 2022; 30:619–26). The first documented use of quinine to treat dermatological conditions was produced by Payne in 1894, who reported the successful treatment of skin lesions in discoid lupus erythematosus (Payne J. A postgraduate lecture on lupus erythematosus Clin J 1894; 4:223–9). In 1951, a case series in the Lancet of 20 patients with lupus erythematosus and rheumatoid arthritis who were successfully treated with quinacrine, led to the extensive use of antimalarials to treat skin and joint conditions (Page F. Treatment of lupus erythematosus with mepacrine. Lancet 1951; 258:755–8). This was later succeeded by chloroquine: a synthetic analogue was first synthesized in the 1930s by Hans Andersag. However, it was noted to have significant toxicities, which led to the production of hydroxychloroquine, a similar drug with a much-improved side-effect profile. After 400 years, quinine and its synthetic derivatives continue to play a major role in managing dermatological conditions.

H20 Gin or tonic: the dermatological hazards of cocktail-based quinine

Abstract Derived from Cinchona tree bark, quinine was first found to be beneficial to health by indigenous Amazonian peoples. Seventeenth-century Jesuit missionaries sent the bark and seeds back to Europe, where word of its therapeutic properties spread. Quinine was promoted as an antiseptic treatment for a range of ailments from the 1600s onward, including septicaemia, erysipelas and scarlet fever. The dermatological risks of quinine quickly became recognized, with Bartholow stating in his 1876 work that ‘The action of quinia has occasionally been attended by the appearance of an eruption on the skin. Sometimes the exanthem has been in the form of an erythema, sometimes it has assumed the appearance of urticaria.’ The pharmacological properties of quinine were exploited by colonial institutions such as the East India Company, who combined a pragmatic approach to antimalarial prophylaxis with a British penchant for aperitivos. The bitter taste of quinine in tonic water led to the addition of water, sugar, lime and gin, giving rise to the gin and tonic (G&T). Its enduring popularity is, in part, due to the astringent nature of quinine and its acidic content that acts as a ‘stomachic tonic; that is, promote appetite, the flow of gastric juice, and the digestive power’. However, since its advent, the G&T has been attributed to many cases of dermatological malaise, as discovered by this systemic review of the published PubMed and SCOPUS literature. To the adage ‘new drugs, new eruptions’, the G&T was no exception. The first published skin reaction to quinine in tonic water dates from 1955, occurring shortly after the patient attended a cocktail party after which they developed ‘a burning sensation in the groins and in his hands and feet’ with progressive oedema and erythema to these areas, spreading to involve nearly all of the body. Other published cases describe (in decreasing frequency) fixed drug eruptions, photosensitive reactions, allergic urticaria and lichenoid drug reactions triggered by quinine in G&Ts. The spectrum of eruptions triggered by tonic water extends to Stevens–Johnson syndrome/toxic epidermal necrolysis triggered by scotch and tonic water consumed at the patient’s peril during a convention in 1972. With an enduring popularity spanning two centuries, and a declaration from Churchill that ‘the gin and tonic has saved more Englishmen's lives, and minds, than all the doctors in the Empire,’ it is vital that dermatologists are aware of the potential dermatological hazards of the G&T.

Synthesis, Anti-Oomycete and Anti-fungal Activities of Novel Cinchona Alkaloid Derivatives Containing Sulfonate Moiety.

Using cinchona alkaloid as the lead compound, twenty-four cinchona alkaloid sulfonate derivatives (1 a-l, 2 a-c, 3 a-c, 4 a-c, and 5 a-c) were designed and prepared by modifying their C9 position, and structurally confirmed by 1 H-NMR, 13 C-NMR, HR-MS and melting points. Moreover, the stereochemical configurations of compounds 1 f and 1 l were unambiguously confirmed by single-crystal X-ray diffraction. Furthermore, we determined the anti-oomycete and anti-fungal activities of these target compounds against Phytophthora capsici and Fusarium graminearum in vitro. The results showed that two compounds 4 b and 4 c exhibited prominent anti-oomycete activity, and the median effective concentration (EC50 ) values of 4 b and 4 c against P. capsici were 22.55 and 16.32 mg/L, respectively. This study suggested that when the C9 position of cinchona alkaloid sulfonate derivatives is in the S configuration and the 6'-position methoxy group is not present, the anti-oomycete activity is superior. In addition, five compounds 1 e, 1 f, 1 k, 3 c and 4 c displayed significant anti-fungal activity, with EC50 values of 43.64, 45.07, 80.18, 48.58 and 41.88 mg/L against F. graminearum, respectively. This result indicates that only when a specific substituent is introduced into the structural framework of the target compound, the corresponding compound exhibits significant inhibitory activity against fungi.

Enantioselective trifluoromethylthiolation of 4-substituted pyrazolones catalyzed by amide-based phase transfer catalysts

We successfully developed the first enantioselective trifluoromethylthiolation of 4-substituted pyrazolones catalyzed by amide-based Cinchona alkaloids with N-trifluoromethylthiosaccharin. A broad variety of chiral CF3S-pyrazolones were obtained in excellent yields with high enantioselectivities. Controlled experiments showed that the multiple hydrogen bonding interactions and the steric hindrance at NH-position were indispensable for high enantioselectivity and reactivity. Furthermore, these amide-based phase transfer catalysts could be easily recovered and reused for such a reaction with almost original reactivity and enantioselectivity.