Quinoline Alkaloids Research Articles

Syntheses of Aristotelia Alkaloids: Reflections in the Chiral Pool.

The Aristotelia alkaloids are a family of monoterpene indole alkaloids possessing a characteristic azabicyclononane scaffold, which has been assembled by several synthetic methods. Herein we review those approaches that have adopted a biomimetic approach to unite heterocyclic synthons with chiral pool monoterpenes. Throughout this discussion, the tendency of monoterpenes like α-pinene and limonene to undergo racemization is highlighted, revealing the challenges in developing stereospecific syntheses of these alkaloids. Finally, we provide a brief discussion of how these synthetic efforts have enabled the structural confirmation and elucidation of the Aristotelia alkaloids' absolute configurations, including our own recent efforts to employ bioactivity data to deduce the naturally occurring configuration of the quinoline alkaloid aristoquinoline.

Combined LC-MS/MS and Molecular Networking Approach Reveals Antioxidant and Antimicrobial Compounds from Erismadelphus exsul Bark.

Erismadelphus exsul Mildbr bark is widely used in Gabonese folk medicine. However, little is known about the active compounds associated with its biological activities. In the present study, phytochemical profiling of the ethanolic extract of Erismadelphus exsul was performed using a de-replication strategy by coupling HPLC-ESI-Q/TOF with a molecular network approach. Eight families of natural compounds were putatively identified, including cyclopeptide alkaloids, esterified amino acids, isoflavonoid- and flavonoid-type polyphenols, glycerophospholipids, steroids and their derivatives, and quinoline alkaloids. All these compounds were identified for the first time in this plant. The use of molecular networking obtained a detailed phytochemical overview of this species. Furthermore, antioxidant (2,2-diphenyl-1-picryl-hydrazylhydrate (DPPH) and ferric reducing capacity (FRAP)) and in vitro antimicrobial activities were assessed. The crude extract, as well as fractions obtained from Erismadelphus exsul, showed a better reactivity to FRAP than DPPH. The fractions were two to four times more antioxidant than ascorbic acid while reacting to FRAP, and there was two to nine times less antioxidant than this reference while reacting to DPPH. In addition, several fractions and the crude extract exhibited a significant anti-oomycete activity towards the Solanaceae phytopathogen Phytophthora infestans in vitro, and, at a lower extent, the antifungal activity against the wheat pathogen Zymoseptoria tritici had growth inhibition rates ranging from 0 to 100%, depending on the tested concentration. This study provides new insights into the phytochemical characterization and the bioactivities of ethanolic extract from Erismadelphus exsul bark.

Discovery of novel benzofuro[3,2-b]quinoline derivatives as dual CDK2/Topo I inhibitors

Uncontrolled cell proliferation is a hallmark of cancer. The major regulator of the cell cycle, cyclin dependent kinase 2 (CDK2), has become a mature target for cancer treatment. Herein, we describe our efforts toward the discovery of a series of benzofuro[3,2-b]quinoline alkaloid derivatives as CDK2 inhibitors through a scaffold hopping strategy. Compound ZLHQ-5f has topoisomerase I (Topo I) inhibitory activity due to the unique structure of benzofurano[3,2-b]quinoline. Resultantly, ZLHQ-5f exhibited promising anti-proliferative and CDK2 inhibitory activities. It also arrests the cell cycle in S-phase, triggers apoptosis in HCT116 cells, and has a good safety profile in vivo. There has yet to be a report on dual CDK2/Topo I inhibitor, thus this will be a novel attempt.

Computational NMR of natural products

This review generalizes diverse computational NMR studies of different natural products involving true alkaloids (indole, quinolizidine, pyrrolizidine, piperidine, indolizidine, quinoline, isoquinoline, indoloquinoline, and guanidine alkaloids), pseudoalkaloids (terpenes and steroids), quinones, lactones, lactams, flavonoids, and many others. The diverse computational protocols employed in each particular case are thoroughly discussed with a special emphasis on their structural and stereochemical applications.The bibliography includes 165 references.

Development and Validation of an Ion-Pair HPLC-UV Method for the Quantitation of Quinoline and Indoloquinoline Alkaloids in Herbal and Pharmaceutical Antimalarial Formulations

Quinine- and cryptolepine-based antimalarials serve as valuable alternatives to artemisinin-based combination therapies (ACTs) in Ghana. Their use, however, is associated with adulteration and substandard quality challenges. An HPLC method targeting quinoline and indoloquinoline antimalarial alkaloids was developed, validated, and applied to evaluate herbal and pharmaceutical antimalarial formulations (HPAFs) and starting materials (APIs). The separation/quantitation of the alkaloids (including quinine, quinidine, cinchonine, cinchonidine, dihydroquinine, dihydroquinidine, and cryptolepine) was achieved on a Zorbax SB-CN column (250 mm × 4.6 mm, 5 μm), with an isocratic elution system of methanol: trifluoroacetic acid (0.1%, v/v) (15 : 85, v/v) at 1.5 mL/min and 223 nm. Method validation was according to ICH Q2(R1) guidelines. It was then used to assess the quality of APIs (n = 3) and HPAFs (n = 44) including quinine-based pharmaceutical antimalarial formulations (QBPAFs) (n = 23) and herbal antimalarial products (HAMPs). The method was found to be specific, selective, accurate, precise, and robust toward the alkaloids with linearity achieved within specified concentration ranges (r2 > 0.995 for all analytes). Analyte stability ranged between 6 and 12 hours. All the APIs contained quinine <99.0%–101.0%, with dihydroquinine and cinchonidine at levels compliant with the established acceptance criteria. The QBPAFs had quinine content ranging between 50.2% and 151.2%, with 43.5% (n = 10/23) of them complying with the acceptance criteria. The related alkaloids observed in the QBPAFs included quinidine (56.5%, n = 13/23), dihydroquinine (100%, n = 23/23), dihydroquinidine (21.7%, n = 5/23), cinchonine (17.4%, n = 4/23), and cinchonidine (95.7%, n = 22/23). For the HAMPs, 81.0% (n = 17/21) were adulterated with quinine (0.59 ± 0.04 mg/10 mL–86.03 ± 0.02 mg/10 mL). Cryptolepine was identified in 19% (n = 4/21) of the HAMPs with concentration ranging between 43.99 ± 0.43 μg/mL and 747.86 ± 0.34 μg/mL. In conclusion, the application of the ion-pair HPLC method targeting quinoline and indoloquinoline antimalarials has demonstrated the presence of quality and poor-quality HPAFs on the Ghanaian market.

Formulation of Cinchona Extract (Cinchona succirubra) Cream and The Safety as Hair Fertilizer

Background: cinchona extract contains quinoline alkaloids, has telangiectatic activity, is practically insoluble in water so penetration into hair follicles is low and requires a delivery system, namely cream. Objective: to determine the formula of cinchona extract cream with good activity, physical stability and safety. Methodology: cinchona bark extraction (soxhletation method), phytochemical screening, cinchona extract dosage determination, optimization of cream formula using Design Expert software version 11. Evaluation: pH, adhesion, spreadability, viscosity and cycling test stability. Activity test using guinea pigs (Cavia porcellus) for 14 days, parameters of hair length/2 days, hair mass (14th day). Acute dermal irritation test using rabbit (Orycogalus cuniculus) by erythema and edema index parameters. Results: cinchona extract (13.32% yield) contained quinoline alkaloids, cinchona extract dosage was 20% (p<0.05). The optimum formula is F2 with characteristics: pH 6.48±0.07, adhesion 1.16±0.07, spreadability 4.99±0.85 and viscosity 3067±416.45, has good physical stability. Activity test: test area hair length 13.54 – 62.14% longer than normal control and 10.10 – 49.17% than negative control. The hair mass of test area was 122.91% heavier than normal control and 104.48% of negative control (p<0.05). Cinchona extract and excipients were non-irritant. Conclusion: Cinchona extract cream (20%) has hair fertilizer activity, good physical stability and safety.

Biology of quinoline and quinazoline alkaloids.

Quinoline and quinazoline alkaloids, two important classes of N-based heterocyclic compounds, have attracted scientific and popular interest worldwide since the 19th century. More than 600 compounds have been isolated from nature to date. To build on our two prior reviews, we reexamined the promising molecules described in previous reports and provided updated literature on novel quinoline and quinazoline alkaloids isolated over the past 5 years. This chapter reviews and discusses 205 molecules with a broad range of bioactivities, including antiparasitic and insecticidal, antibacterial and antifungal, cardioprotective, antiviral, anti-inflammatory, and other effects. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids.

Three New Quinoline Alkaloids from the Whole Plant of Thalictrum atriplex and Their Bioactivities

Three New Quinoline Alkaloids from the Whole Plant of Thalictrum atriplex and Their Bioactivities

Dictamnine inhibits pancreatic cancer cell growth and epithelial-mesenchymal transition by blocking the PI3K/AKT signaling pathway.

Many different treatments are available for pancreatic cancer (PC), including surgical resection, chemotherapy, radiotherapy, and immunotherapy, but these treatments are often ineffective at curing PC. Hence, identifying new and effective agents or strategies to improve therapeutic effects is critical. This study focused on the efficacy of dictamnine (DTM), a furan quinoline alkaloid extracted from Dictamnus dasycarpus Turcz., in treating PC. Our in vitro results showed that DTM can mitigate cell proliferation and induce cell cycle arrest and apoptosis in two different human PC cell lines. Moreover, epithelial-mesenchymal transition (EMT) was prevented during DTM treatment, reflected by reduced cell migration and invasion abilities. In vivo studies demonstrated that DTM treatment led to a remarkable inhibition of tumor growth in a xenograft nude mouse model. Mechanistic investigation showed that DTM might act by restraining constitutive and induced PI3K/AKT activity. In summary, our results demonstrated that DTM slows PC progression by inhibiting the activity of the PI3K/AKT signaling pathway and its downstream effectors and that DTM is effective as a pathway-specific cancer therapy. These findings could provide a greater understanding of the function of anticancer drugs and new options for PC treatment.

Quinoline alkaloids with anti-inflammatory activity from Zanthoxylum avicennae.

Zanthoxylum avicennae fruits were traditionally used to treat many inflammatory-related diseases, such as icterohepatitis, nephritis and colitis, which inspired us to explore the active chemicals and pharmacological activity. As a result, ten quinoline alkaloids, including six new ones, avicenines A-F (1-6), were isolated and structurally characterized by solid data. Compounds 1, 7 and 8 were identified as three pairs of enantiomers by chiral HPLC separation, of which 1 was an unusual 6/6/5/5-fused quinoline alkaloid bearing a unique cis-hexahydrofuro[3,2-b]furan moiety. The putative biosynthetic pathway for enantiomeric compounds was also proposed. In addition, compound 6 significantly suppressed the gene expression and secretion of pro-inflammatory cytokines IL-1β and IL-6 in macrophages.

Two New Anti-Tobacco Mosaic Virus Quinoline Alkaloids from the Stems of Nicotiana tabacum

Two New Anti-Tobacco Mosaic Virus Quinoline Alkaloids from the Stems of Nicotiana tabacum

A quinoline alkaloid potentially modulates the amyloidogenic structural transitions of the biofilm scaffolding small basic protein

Bacterial biofilm formation by communities of opportunistic bacterial pathogens like Staphylococcus epidermidis is regarded as the primary virulence mechanism facilitating the spread of detrimental nosocomial and implant-associated infections. An 18-kDa small basic protein (Sbp) and its amyloid fibrils account for strengthening the biofilm architecture and scaffolding the S. epidermidis biofilm matrix. Our study reports systematic analysis of the amyloidogenic structural transitions of Sbp and predicts the amyloid core of the protein which may trigger misfolding and aggregation. Herein, we report the novel amyloid inhibitory potential of Camptothecin, a quinoline alkaloid which binds stably to Sbp monomers and redirects the formation of unstructured regions further destabilizing the protein. Molecular dynamics simulations reveal that Camptothecin averts β-sheet transitions, interrupts with electrostatic interactions and disrupts the intermolecular hydrophobic associations between the exposed hydrophobic amyloidogenic regions of Sbp. Collectively, our study puts forward the first report detailing the heteromolecular associations and amyloid modulatory effects of Camptothecin which may serve as a structural scaffold for the tailored designing of novel drugs targeting the S. epidermidis biofilm matrix. Communicated by Ramaswamy H. Sarma

Study of Molecular Docking, Molecular Dynamic and Toxicity Prediction of Several Quinoline Alkaloid Derivatives as a Bruton Tyrosine Kinase Inhibitor as Anti-Leukemia

Quinoline alkaloid and its derivatives play a vital role in the development of new therapeutic agents. Cinnoline structure has similarities with quinoline alkaloid compound and has the potential to inhibit Bruton’s Tyrosine Kinase (BTK) in leukemia treatment. This research aims to study the interaction of several quinoline alkaloids with BTK and to predict the toxicity to ensure their safety. This study was carried out using computational studies, including molecular docking, molecular dynamics simulation, and toxicity prediction, to assess the compound’s activity towards BTK and their toxicity. Molecular docking simulations showed that ten compounds (S1, S2, S4, S5, S8, S13, S14, S16, S17, and S20) had the best affinity to BTK. Molecular dynamics simulations to these ten compounds showed that only seven compounds (S1, S5, S8, S13, S16, S17, and S20) could stabilize the interaction towards BTK with RMSD and RMSF value of 0.5 ± 2 Å and 0.5 ± 6, 5 Å, respectively. Toxicity prediction results showed that these quinoline alkaloids had various toxicity characteristics, but most were not carcinogens and mutagens (S4, S5, S6, S7, S8, S10 S11, S12, S14, and S15). It can be concluded that Yukositrin (S8) has the most potential affinity towards BTK, which can be used as anti-leukemia with low toxicity.
 Keywords: anti-leukemia, Bruton Tyrosine Kinase, docking, MD, quinoline alkaloids

Discovering and harnessing oxidative enzymes for chemoenzymatic synthesis and diversification of anticancer camptothecin analogues

Semi-synthetic derivatives of camptothecin, a quinoline alkaloid found in the Camptotheca acuminata tree, are potent anticancer agents. Here we discovered two C. acuminata cytochrome P450 monooxygenases that catalyze regio-specific 10- and 11-oxidations of camptothecin, and demonstrated combinatorial chemoenzymatic C-H functionalizations of the camptothecin scaffold using the new enzymes to produce a suite of anticancer drugs, including topotecan (Hycamtin®) and irinotecan (Camptosar®). This work sheds new light into camptothecin metabolism, and represents greener approaches for accessing clinically relevant camptothecin derivatives.

Catalytic Asymmetric Halogenation/Semipinacol Rearrangement of 3‐Hydroxyl‐3‐vinyl Oxindoles: A Stereodivergent Kinetic Resolution Process

AbstractA highly enantioselective halogenation/semipinacol rearrangement of isatin‐derived allylic alcohols has been developed with a chiral N,N′‐dioxide/ScIII complex as catalyst. This strategy involved a pivotal stereodivergent kinetic resolution process and provided a facile and efficient entry to optically active halo‐substituted quinolone derivatives and quinoline alkaloids with a quaternary stereocenter simultaneously under mild reaction conditions. Based on the control experiments together with kinetic studies and DFT calculations, a possible catalytic cycle was proposed to illustrate the reaction process and enantiocontrol.

Catalytic Asymmetric Halogenation/Semipinacol Rearrangement of 3-Hydroxyl-3-vinyl Oxindoles: A Stereodivergent Kinetic Resolution Process.

A highly enantioselective halogenation/semipinacol rearrangement of isatin-derived allylic alcohols has been developed with a chiral N,N'-dioxide/ScIII complex as catalyst. This strategy involved a pivotal stereodivergent kinetic resolution process and provided a facile and efficient entry to optically active halo-substituted quinolone derivatives and quinoline alkaloids with a quaternary stereocenter simultaneously under mild reaction conditions. Based on the control experiments together with kinetic studies and DFT calculations, a possible catalytic cycle was proposed to illustrate the reaction process and enantiocontrol.

Neuroprotective potential of berberine in modulating Alzheimer's disease via multiple signaling pathways.

Berberine is one of the most important quinoline alkaloids, which has shown numerous pharmacological activities. There are pieces of evidence that berberine serves as a promising substance for treating Alzheimer's disease (AD). Recently, numerous studies on animal models have shown the neuroprotective role of berberine. AD is a complex disease having multiple pathological factors. Berberine restrains the deposition of amyloid plaques and neurofibrillary tangles. Substantial studies have demonstrated that berberine may also exhibit the protective effect against the risk factors associated with AD. This review illustrates the role of berberine in neuroinflammation, oxidative stress and its activity against acetylcholinesterase enzyme. It also focuses on the bioavailability and safety of berberine in AD. However, more investigations are required to explore the bioavailability and safety assessment of berberine and its new perspectives in limiting the AD-related pathogenesis and risk factors. PRACTICAL APPLICATIONS: Current therapeutic measures only provide symptomatic relief against AD by slowing memory loss, resolving thinking problems and behavioral issues. In recent past years, many biological actions and potential therapeutic applications have been observed by berberine particularly in neurological diseases. Berberine has been investigated by various researchers for its activity against AD. This review demonstrates a variety of mechanisms by which berberine imparts its neuroprotective roles and provides the possible mechanism of action of berberine by which it prevents the formation of neurofibrillary tangles and disaggregation of amyloid beta plaques in AD. It also focuses that berberine limits the neuroinflammation and oxidative stress in AD. Pre-clinical aspects of berberine against AD are also discussed. Eventually, a prospect is formulated that berberine might be a therapeutically significant agent for treating and preventing AD.

Five new quinoline alkaloids from Sauropus hirsutus Beille and their cytotoxicity

Chemical investigation of the whole plant of Sauropus hirsutus Beille led to the isolation of eight quinolines and two known flavonoids. Furthermore, five quinolines were new, two were reported in plant for the first time and one was known. Cytotoxicity evaluation against cholangiocarcinoma, KKU-M156, showed that the most active compound was 4-hydroxy-6-methoxy-7,8-methylenedioxyquinaldine (IC50 20.54 ± 6.82 µM) which was a little more active than the cisplatin standard (IC50 24.39 ± 1.14 µM).

An Overview of COVID-19 and the Potential Plant Harboured Secondary Metabolites against SARS-CoV-2: A Review

The SARS-CoV-2 virus causes COVID-19, a pandemic disease, and it is called the novel coronavirus. It belongs to the Coronaviridae family and has been plagued the world since the end of 2019. Viral infection to the lungs causes fluid filling and breathing difficulties, which leads to pneumonia. Pneumonia progresses to ARDS (Acute Respiratory Distress Syndrome), in which fluid fills the air sac and seeps from the pulmonary veins. In the current scenario, several vaccines have been used to control the pandemic worldwide. Even though vaccines are available and their effectiveness is short, it may be helpful to curb the pandemic, but long-term protection is inevitable when we look for other options. Plants have diversified components such as primary and secondary metabolites. These molecules show several activities such as anti-microbial, anti-cancer, anti-helminthic. In addition, these molecules have good binding ability to the SARS-CoV-2 virus proteins such as RdRp (RNA-dependent RNA polymerase), Mpro (Main Protease), etc. Therefore, these herbal molecules could probably be used to control the COVID-19. However, pre-requisite tests, such as cytotoxicity, in vivo, and human experimental studies, are required before plant molecules can be used as potent drugs. Plant metabolites such as alkaloids, isoquinoline ß-carboline, and quinoline alkaloids such as skimmianine, quinine, cinchonine, and dictamine are present in plants and used in a traditional medicinal system.

Construction of N-Heterocycles Fused with a Highly Substituted Benzene Ring by a Benzyne-Mediated Cyclization/Functionalization Cascade Reaction and Its Application to the Total Synthesis of Marine Natural Products.

This account summarizes the development of a benzyne-mediated cyclization/functionalization protocol for the versatile construction of highly substituted benzene derivatives fused with an N-heterocyclic ring such as indolines, indoles, and related nitrogen-containing heterocycles. The protocol comprises sequential reactions initiated by generating a benzyne species and subsequent cyclization via addition of magnesium amide to the benzyne, followed by trapping of the resultant magnesium compound in situ with various electrophiles. The substituent scope was expanded by conducting a transmetalation on a copper species to introduce alkyl, aryl, and alkenyl substituents. The utility of the sequential reaction was demonstrated in the synthesis of a carbazole natural product (heptaphylline), pyrrolo[4,3,2-de]quinoline alkaloids (batzellines), and pyrrolo[2,3-c]carbazole alkaloids (dictyodendrines).