Alkaloid Derivatives Research Articles

Abstract- Poster

INTRODUCTIONBuprenorphine, a semi-synthetic opiate alkaloid derivative used for treatment of opioid dependence(1). Pruritis has been reported as a side effect with intramuscular and supra-dermal patch of buprenorphine and less common with oral/sublingual use of Buprenorphine.CASE REPORT19 years male presented to OPD of a tertiary care center with history of consuming smack in a chasing pattern for past 9 years, associated with tolerance, withdrawal, inability control the urge, craving and significant socio-occupational dysfunction due to opioid use. He had past history of conduct disorder. Patient was diagnosed with Mental and behavioral disorder due to opioid use, dependent pattern (ICD-10). For opioid substitution he was initiated with tablet buprenorphine sublingual (4 mg), after 1 day later he developed skin reaction- itching and erythema and then vesicular lesion. Consultation liaison with Dermatology department was done for evaluation of the allergic reaction and a drug re-challenge trial to assess for hypersensitivity was done with informed written consent of patient. There was increase in eosinophil counts from a differential count of 5% to 15% after re-administration of sublingual Buprenorphine suggestive of opioid related allergic dermatitis. The symptoms of intermittent itching was reported and managed with Tablet cetirizine 10 mg and local applicant Mometasone and Fusidic acid combination. However, on discontinuation of tablet buprenorphine new lesion didn't erupt whereas old lesion gradually healed. His Buprenorphine was discontinued and symptomatic management was done for withdrawal symptoms.DISCUSSIONThe aetiology of opioid-induced itching is unknown but may be due to either a direct central effect or to histamine release. Reports of allergic contact dermatitis are common with Buprenorphine patch, though uncommon with sublingual Buprenorphine use.CONCLUSIONThe present report describes allergic dermatitis is an uncommon drug reaction with sublingual Buprenorphine use and hence should be dealt vigilantly.

Synthesis and antiprotozoal activity of peganine alkaloid derivatives

Synthesis and antiprotozoal activity of peganine alkaloid derivatives

Discovery of Novel Quindoline Alkaloids Derivatives as Dual CDK2/Topo I Inhibitors

Discovery of Novel Quindoline Alkaloids Derivatives as Dual CDK2/Topo I Inhibitors

Synthesis and antihyperlipidaemic activity of a new piperine derivative

Long pepper (Piper longum Linn.) is widely used as a medicinal substance in traditional Ayurvedic medicine. Its major alkaloid piperine is the main active constituent with various therapeutic activities and has low solubility in water. In this study, a soluble new derivative of a piperine alkaloid, named N-leucinylpiperamide was synthesized. The animal experiment showed that N-leucinylpiperamide has more hypolipidemic effects than commercially available simvastatin and piperine in modulating serum lipids in Wistar male rats. At the amount of 10 mg/kg bw, it significantly reduced TC (-52.4%), TG (-61.7%), and LDL-C (-27.8%), respectively, and increased HDL-C (+147.4%) in the serum of the high-lipid model group. Furthermore, the synthesized N-leucinylpiperamide had no noticeable cytotoxicity against HepG2 cell line in vitro. Thus, our study shows that N-leucinylpiperamide has an ability to improve serum lipid profile in hyperlipidemic model rats and could be a valuable promising agent for the preventing hyperlipidemia.

Antiviral Activities of Carbazole Derivatives against Porcine Epidemic Diarrhea Virus In Vitro.

Porcine epidemic diarrhea virus (PEDV), an enteric coronavirus, causes neonatal pig acute gastrointestinal infection with a characterization of severe diarrhea, vomiting, high morbidity, and high mortality, resulting in tremendous damages to the swine industry. Neither specific antiviral drugs nor effective vaccines are available, posing a high priority to screen antiviral drugs. The aim of this study is to investigate anti-PEDV effects of carbazole alkaloid derivatives. Eighteen carbazole derivatives (No.1 to No.18) were synthesized, and No.5, No.7, and No.18 were identified to markedly reduce the replication of enhanced green fluorescent protein (EGFP) inserted-PEDV, and the mRNA level of PEDV N. Flow cytometry assay, coupled with CCK8 assay, confirmed No.7 and No.18 carbazole derivatives displayed high inhibition effects with low cell toxicity. Furthermore, time course analysis indicated No.7 and No.18 carbazole derivatives exerted inhibition at the early stage of the viral life cycle. Collectively, the analysis underlines the benefit of carbazole derivatives as potential inhibitors of PEDV, and provides candidates for the development of novel therapeutic agents.

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

CYCLODEXTRIN INCLUSION COMPLEXES OF PHARMACEUTICALLY ACTIVE DERIVATIVES OF THE CYTISINE ALKALOID AND THEIR HEMORHEOLOGICAL ACTIVITY

The alkaloid cytisine is of great importance for modern pharmacological studies. This alkaloid can be used as a component of the supramolecular system with cyclic oligosaccharides, namely β-cyclodextrins, which have a truncated cone-shaped molecule with internal protons Н3 and Н5 and external ones Н2 and Н4. The aim of the work is to obtain inclusion complexes of pharmaceutically active derivatives of the alkaloid cytisine. The inclusion complexes of cytisine alkaloid derivatives with β-CD and 2-HP-β-CD were obtained by the coprecipitation method. Thermogravimetric, differential thermal, and differential scanning calorimetric analyzes were performed. It was shown that inclusion complexes of substrate with cyclodextrin cavity of receptors were formed. The greatest change in the chemical shifts of protons during the formation of supra-molecular complexes occurs with the internal protons H-3 and H-5 of the cyclodextrin cavity. All calculated values are in good agreement with experimental data. The prepa-ration of supramolecular complexes has been proven using a variety of physicochemical methods of analysis. According to DSC data, the process of complexes destruction in the temperature range of 30-610°C was studied in comparison with the data of the initial cyclodextrin. The hemorheological effects of the investigated samples were studied in vitro. Among four samples studied, two samples showed the ability to reduce blood viscosity in vitro in the blood hyperviscosity model.

Construction of a Protoberberine Alkaloid Skeleton via the Palladium-Catalyzed α-Arylation-Amide Formation Cascade.

In this work, we report the strategy of one-pot synthesis of protoberberine alkaloid derivatives via palladium-catalyzed cascade α-arylation and cyclization, which can afford the target molecules in moderate to excellent isolated yields using commercially available raw materials under solvent-free conditions. This protocol provides an efficient and convenient path to multisubstituted protoberberine derivatives. In addition, it can directly afford natural alkaloids.

New N-methyl-4-quinolone alkaloid and citrinin dimer derivatives from the sponge-derived fungus Penicillium sp. SCSIO 41303

Four new N-methyl-4-quinolones (1–4) and a new citrinin dimer derivative (10) with fourteen known compounds (5–9, 11–19) were isolated from the sponge-derived fungus Penicillium sp. SCSIO41303. Their structures and absolute configurations were elucidated by extensive spectroscopic analysis, electronic circular dichroism (ECD) calculation, and X-ray single-crystal diffraction. Most of the isolated compounds were evaluated for their cytotoxic, antibacterial, anti-virus, and enzyme inhibitory activities against acetylcholinesterase (AChE), and pancreatic lipase (PL). Compounds 2 and 11 exhibited enzyme inhibition activity against PL with IC50 values of 24.6 and 7.2 μg/mL, respectively. Besides, compound 11 showed enzyme inhibition activity against AChE with IC50 value of 16.5 μg/mL. Compound 15 showed moderate inhibition activities with 52.2% at the concentration of 50 μg/mL against PL and antibacterial activity against Staphylococcus aureus displaying diameter of about 10 mm.

One-pot synthesis and biological evaluation of (2E,4E)-4-arylidene-2-styryl-5-oxopyrrolidine derivatives

Many marine alkaloids possess interesting structures and antitumor activities. Thus, we have synthesized (2 E,4 E)-4-arylidene-2-styryl-5-oxopyrrolidine derivatives of the marine alkaloids, rhopaladins A–D. The cytotoxicities of these derivatives against C-33A, CaSki, SiHa, HeLa, HepG2, and LO2 cells are evaluated by MTT assays. The results show that (2 E,4 E)-2-(4-chlorostyryl)-4-benzylidene- N-cyclohexyl-1-(4-fluorophenyl)-5-oxopyrrolidine-2-carboxamide significantly inhibits cancer cell proliferation, with IC50values against C-33A, CaSki, SiHa, HeLa, and HepG2 cells of 5.56, 9.15, 12.5, 21.4, and 14.5 μM, respectively, and an IC50value of 86.77 μM against the normal LO2 cell line.

Isosteroidal alkaloids from Fritillaria hupehensis Hsiao et K.C.Hsia: Synthesis and biological evaluation of alkaloid derivatives as potential cytotoxic agents

One new cevanine isosteroidal alkaloid named 5,6-anhydrohupehenine (1), together with five known alkaloids (2–6) were isolated from Fritillaria hupehensis Hsiao et K.C.Hsia, among which 5,6-anhydrohupehenine (1) exhibited strong inhibitory activity against HepG2 (IC50 = 12.21 μM) and MCF-7 (IC50 = 22.05 μM) cancer cells. Therefore, a total of 33 5,6-anhydrohupehenine derivatives (9a-9s, 10a-10f, 11a-11b, and 12a-12f) were synthesized and evaluated for their cytotoxic activity. The cytotoxicity evaluation of all 5,6-anhydrohupehenine derivatives against HepG2 and MCF-7 human cancer cells revealed that 9s displayed best activity against HepG2 cells with IC50 at 1.27 μM. Further biological evaluations on 9s showed that it inhibited the proliferation of HepG2 cells and induced apoptosis of the HepG2 cells by activating cleaved caspase-3. Moreover, 9s exhibited strong antimetastatic potential. These results suggest that 5,6-anhydrohupehenine is a promising compound to be designed as novel cytotoxic agents.

Cinchona Alkaloid-Inspired Urea-Containing Autophagy Inhibitor Shows Single-Agent Anticancer Efficacy.

Autophagy is upregulated in response to metabolic stress, a hypoxic tumor microenvironment, and therapeutic stress in various cancers and mediates tumor progression and resistance to cancer therapy. Herein, we identified a cinchona alkaloid derivative containing urea (C1), which exhibited potential cytotoxicity and inhibited autophagy in hepatocellular carcinoma (HCC) cells. We showed that C1 not only induced apoptosis but also blocked autophagy in HCC cells, as indicated by the increased expression of LC3-II and p62, inhibition of autophagosome-lysosome fusion, and suppression of the Akt/mTOR/S6k pathway in the HCC cells. Finally, to improve its solubility and efficacy, we encapsulated C1 into PEGylated lipid-poly(lactic-co-glycolic acid) (PLGA) nanoscale drug carriers. Systemic administration of nanoscale C1 significantly suppressed primary tumor growth and prevented distant metastasis while maintaining a desirable safety profile. Our findings demonstrate that C1 combines autophagy modulation and apoptosis induction in a single molecule, making it a promising therapeutic option for HCC.

Derivatives of montanine-type alkaloids and their implication for the treatment of Alzheimer's disease: Synthesis, biological activity and in silico study

Alzheimeŕs disease (AD) is the most common neurodegenerative disorder, characterized by neuronal loss and cognitive impairment. Currently, very few drugs are available for AD treatment, and a search for new therapeutics is urgently needed. Thus, in the current study, twenty-eight new derivatives of montanine-type Amaryllidaceae alkaloids were synthesized and evaluated for their ability to inhibit human recombinant acetylcholinesterase (hAChE) and butyrylcholinesterase (hBuChE). Three derivatives (1n, 1o, and 1p) with different substitution patterns demonstrated significant selective inhibitory potency for hAChE (IC50 < 5 µM), and one analog, 1v, showed selective hBuChE inhibition activity (IC50 = 1.73 ± 0.05 µM). The prediction of CNS availability, as disclosed by the BBB score, suggests that the active compounds in this survey should be able pass through the blood–brain barrier (BBB). Cytotoxicity screening and docking studies were carried out for the two most pronounced cholinesterase inhibitors, 1n and 1v.

Trimeric and Dimeric Carbazole Alkaloids from Murraya microphylla.

Seventeen new carbazole alkaloid derivatives, including a trimeric carbazole racemate, (±)-microphyltrine A (1), 15 dimeric carbazole racemates, (±)-microphyldines A–O (2–16), and a C-6–C-3″-methyl-linked dimeric carbazole, microphyldine P (17), were isolated from the leaves and stems of Murraya microphylla (Merr. et Chun) Swingle. The structures of the new compounds were elucidated on the basis of HRESIMS and NMR data analysis. The optically pure isomers of these isolated carbazole alkaloids were obtained by chiral HPLC separation and their absolute configurations were determined by electronic circular dichroism (ECD) data analysis.

Dihydroergotamine affects spatial behavior and neurotransmission in the central nervous system of Wistar rats.

Dihydroergotamine (DHE) is a derivative of an ergot alkaloid used as an antimigraine medication. Nowadays, ergot alkaloids may still endanger the safety of humans and animals as food or medicine pollutants, but the outcomes of long-term DHE administration on the behaviour and neurotransmission remain undescribed. Adult male Wistar Albino Glaxo rats pre-treated orally with DHE for six weeks were investigated to assess the relationship between concentration of neurotransmitters and behavioural response. The behavioural effects of the drug administered at doses of either 30 µg/kg b.w. (group DHE30, n = 11) or 100 µg/kg b.w. per day (group DHE100, n = 10) were evaluated in the Morris Water Maze. It is known that monoaminergic neurotransmitters (serotonin, noradrenaline and dopamine) in some brain structures (prefrontal cortex, hippocampus, striatum, cerebellum, spinal cord) play a role in the control of cognitive and motor functions. The concentration of neurotransmitters was determined by High Performance Liquid Chromatography (HPLC). Administration of DHE influenced neither the learning processes nor memory in rats. Nevertheless, an increased motor activity of the DHE-administered animals was observed in both the cued and non-cued behavioural tasks. In HPLC examination, changes in the concentration of monoaminergic neurotransmitters and their metabolites were noted in all tested structures, except for the hippocampus. DHE is able to modulate noradrenergic, serotonergic and dopaminergic neurotransmission that may support the increase in locomotion.

Synthesis and Antimicrobial Evaluation of Calycanthaceous Alkaloid Derivatives

Synthesis and Antimicrobial Evaluation of Calycanthaceous Alkaloid Derivatives

Identification of Two Novel CIL-102 Upregulations of ERP29 and FUMH to Inhibit the Migration and Invasiveness of Colorectal Cancer Cells by Using the Proteomic Approach.

CIL-102 (1-[4-(furo[2,3-b]quinolin-4-ylamino) phenyl]ethanone) is a major active agent of Camptotheca acuminata’s alkaloid derivative, and its anti-tumorigenic activity, a valuable biological property of the agent, has been reported in many types of cancer. In this study, we researched the novel CIL-102-induced protein for either the induction of cell apoptosis or the inhibition of cell migration/invasiveness in colorectal cancer cells (CRC) and their molecular mechanism. Firstly, our data showed that CIL-102 treatment not only increased the cytotoxicity of cells and the production of Reactive Oxygen Species (ROS), but it also decreased cell migration and invasiveness in DLD-1 cells. In addition, many cellular death-related proteins (cleavage caspase 9, cleavage caspase 3, Bcl-2, and TNFR1 and TRAIL) and JNK MAPK/p300 pathways were increased in a time-dependent manner. Using the proteomic approach with a MALDI-TOF-TOF analysis, CIL-102-regulated differentially expressed proteins were identified, including eight downregulated and 11 upregulated proteins. Among them, upregulated Endoplasmic Reticulum resident Protein 29 (ERP29) and Fumarate Hydratase (FUMH) by CIL-102 were blocked by the inhibition of ROS production, JNK activity, and p300/CBP (CREB binding protein) signaling pathways. Importantly, the knockdown of ERP29 and FUMH expression by shRNA abolished the inhibition of cell migration and invasion by CIL-102 in DLD-1 cells. Together, our findings demonstrate that ERP29 and FUMH were upregulated by CIL102 via ROS production, JNK activity, and p300/CBP pathways, and that they were involved in the inhibition of the aggressive status of colorectal cancer cells.

Novel glutamic acid derivatives from the bulbs of Fritillaria verticillate Willd and their antitumor activities

Four previously undescribed glutamic acid derivatives, verticillamines A-D (1–4), together with six known compounds (5–10) were isolated from the bulbs of Fritillaria verticillate Willd. The structures of (1−10) were established on the basis of UV, IR, MS, 1D and 2D NMR, and the absolute configurations of compounds (1–4) were determined by calculated ECD methods. Among them, compounds (1–3) were rare 2-methyl-γ-lactam alkaloid derivatives. Moreover, both γ-lactam alkaloids (1–5) and pyrrolidine alkaloids (6–7) were discovered in Fritillaria for the first time. Compound 8 exhibited moderate cytotoxic activities against A2780 and HepG 2 cells, with IC50 values of 11.7 ± 5.2 μM and 25.6 ± 2.8 μM.

Evaluation of the Phytochemical, Antioxidant, Enzyme Inhibition, and Wound Healing Potential of Calotropis gigantea (L.) Dryand: A Source of a Bioactive Medicinal Product.

Traditionally, plants of the genus Calotropis have been used to cure various common diseases. The present research work explores the chemical and biological characterization of one of the most common species of this genus, i.e., Calotropis gigantea (L.) Dryand (syn. Calotropis gigantea (L.) Dryand.), having multiple folklore applications. The ethanolic extract of leaves of Calotropis gigantea (L.) Dryand was analyzed for the phytochemical composition by determining the total bioactive (total phenolic and total flavonoid) contents and UHPLC-MS secondary metabolites analysis. For phytopharmacological evaluation, in vitro antioxidant (including DPPH, ABTS, FRAP, CUPRAC, phosphomolybdenum, and metal chelation antioxidant assays) activities, enzyme inhibition potential (against AChE, BChE, α-amylase, and tyrosinase enzymes), and in vivo wound healing potential were determined. The tested extract has been shown to contain considerable flavonoid (46.75 mg RE/g extract) and phenolic (33.71 mg GAE/g extract) contents. The plant extract presented considerable antioxidant potential, being the most active for CUPRAC assays. Secondary metabolite UHPLC-MS characterization, in both the positive and negative ionization modes, indicated the tentative presence of 17 different phytocompounds, mostly derivatives of sesquiterpene, alkaloids, and flavonoids. Similarly, the tested extract exhibited considerable inhibitory effects on tyrosinase (81.72 mg KAE/g extract), whereas it showed weak inhibition ability against other tested enzymes. Moreover, in the case of in vivo wound healing assays, significant improvement in wound healing was observed in both the tested models at the doses of 0.5 percent w/w (p < 0.001) and 2.0 percent w/w (p < 0.01) on the 16th day. The outcomes of the present research work suggested that C. gigantea (L.) Dryand plant extract could be appraised as a potential origin of bioactive molecules having multifunctional medicinal uses.

Description of the Mechanism of Positive Inotropic Action of the Isoquinoline Alkaloid F-18

This study evaluated the mechanism of inotropic effect of an isoquinoline alkaloid derivative, 1-(2´-bromine-4´,5´-dimethoxyphenyl)-6,7-dimethoxy-1,2,3,4- tetrahydroisoquinoline (F-18) using electrically stimulated rat left ventricular papillary muscle of rat. The F-18 alkaloid have been shown to have positive inotropic effect on papillary muscle contraction activity, IC50 value -14,6 µM. Са2+L-channel blocker - nifedipine was used in experiments. Inotropic effects of F-18 isoquinoline alkaloid on cardiomyocytes were suggested, based on results obtained in experiments carried in cardiomyocytes SR Ca2+- transport systems modulation.