Current Bioactive Compounds - Volume 19, Issue 6, 2023

Background: Cyclea peltata (Lam.) Hook. f. and Thoms., an ethnomedicinal herb with antitoxin and anti-herpes activities, is used to cure smallpox, wounds, diabetic disorders of the skin, and its use as a cooling agent. In the present study, an attempt has been made to screen different alkaloids present in Cyclea peltata roots using LC-ESI-MS/MS and to evaluate the in vitro cytotoxic activity of alkaloids. Methods: The detection of alkaloids in C. peltata root extract was carried out by performing MRM-based assay using liquid chromatography-mass spectrometry. The cytotoxic effect of the acetone crystalized fraction was performed against human pancreatic cancer using MIA PaCa-2 cells. Results: The study revealed the presence of tetrandrine and fangchinoline as the major BBI alkaloids in the roots of this herb, along with cycleacurine, isochondrodendrine, cycleahomine and tetrandrine mono-N-2’-oxide. Furthermore, the present study also detected two precursors of BBI alkaloids such as d-Coclaurine, (-)-N-methylcoclaurine. The study also showed a significant (p<0.05) cytotoxic effect of the acetone crystalized fraction with an IC50 value of 59.85 μg/ml. Conclusion: C. peltata root is the major source of tetrandrine and fangchinoline with potent cytotoxic effect.

Background: A cellular model of oxidative stress induced by hydrogen peroxide in the primary culture of myoblasts was obtained by in vitro experiments, and the possibility of exogenous regulation of the cytotoxic effect using 2-ethyl-6-methyl-3-hydroxypyridine malate (ethoxidol) was studied. Moreover, the influence of oxidative stress and the effect of ethoxidol on the intracellular expression of such an important biomarker as myostatin was investigated. Methods: Hydrogen peroxide was used to induce oxidative stress. The effect of hydrogen peroxide on the rate of myoblast proliferation was studied by measuring the reduction level of (3-(4,5- dimethylthiazole-2-yl))-2,5-diphenyltetrazolium bromide. To measure the expression of myostatin, a real-time polymerase chain reaction (PCR-RV) method was used. Results: During the work, it was clearly demonstrated that hydrogen peroxide has a significant cytostatic effect on myoblasts in vitro, inhibiting their proliferation. Ethoxidol in physiological concentration did not show toxic effects and did not inhibit cell proliferation. This antioxidant revealed a statistically significant protective effect on the cytostatic effect of hydrogen peroxide on myoblasts. In addition, this compound inhibited the expression of myostatin mRNA caused by exposure to hydrogen peroxide as a negative regulator of growth and differentiation of muscle tissue that occurs in response to exposure to reactive oxygen species. Conclusion: Hydrogen peroxide is one of the highly active forms of oxygen and has a significant cytostatic effect on myoblasts in vitro, suppressing their proliferation. 2-ethyl-6-methyl-3- hydroxypyridine malate neutralizes the toxic effect of peroxide, thereby indirectly having a positive effect on the rate of myoblast proliferation in vitro.

Background: A series of bi-triazoles conjugates 1,2,3 and 1,2,4 was synthesized with an aim to study the evaluation of the antimalarial profile of families of triazole derivatives. The study used the W2 strain of Plasmodium falciparum (Chloroquine-Resistant), to determine the inhibitory concentration of 50% of the parasites (IC50) and HepG2 cells to describe the cytotoxic concentration for 50% of the cells (CC50). Among the study classes, bi-triazoles stood out with IC50 values between 8.9 to 0.45 μM; highlighted the compound 14d (IC50 of 0.45 ± 0.02 μM) with the most promising result. Regarding the cytotoxic concentration, all compounds that presented IC50 values ≤ 100 μM were evaluated. Three compounds stood out as the highest selectivity index (SI) values, 14b (SI #131;111.1), 13d (SI #131;111.1) and 14d (SI #131;1.111). Such results expose the importance of working with classes of molecules that allow rapid synthesis and dispositions for structural changes. Highlighting the evolution of the IC50 values of the compounds, when adding the second triazole block. Thus, the results found in this study, have the possibility of choosing new molecules for the treatment of malaria. Objective: This work was to synthesize a series of bi-triazole conjugates 1,2,3 and 1,2,4-triazole moiety and evaluate their activities against Plasmodium falciparum. Methods: The bi-triazole was synthesized in a 3-step route in moderated yields, and their structures were confirmed by NMR spectral data analyses. For the in vitro antiplasmodial assays, the SYBR Green fluorimetric technique and the W2 strain were used, where an IC50 (Inhibitory Concentration) value was obtained for each compound. The compounds were also evaluated for their stagespecificity and speed of action (W2 strain). Safety tests were performed to determine the hemolytic and cytotoxic action of the evaluated compounds. In these tests, the cell lines HepG2 and VERO were used, and the cytotoxicity was evaluated by the MTT technique. This allowed the CC50 values to be obtained (Cytotoxic Concentration). Subsequently, the Selectivity Index (SI) was calculated for each compound. Results: The newly synthesized bi-triazole compounds could serve as potent leads for the development of novel antimalarial compounds. In general, the bi-triazoles with trifluoromethyl group present at 1,2,4-triazole moiety proved to be more potent regarding antiplasmodial activity. Conclusion: The synthesized bi-triazole compounds could serve as potent leads for the development of novel antimalarial agents.

Background: The necessity for newer anti-microbial medications with prototypes has arisen as a result of the prevalence of infections caused by resistant strains of microorganisms. Objective: A series of nine novel benzothiazole-linked pyrazole prototype derivatives were synthesized in multistep reactions and evaluated for anti-microbial and anti-fungal activities. The druglikeness along with physicochemical properties of synthesized compounds were determined by docking the ligands with resistant strains. Methods: Synthesis of benzothiazole and pyrazole prototype derivatives was carried out by a sequence of reactions to attain the hydrazine carboxamide derivatives. All the synthesized compounds were characterized and evaluated for their anti-bacterial and anti-fungal activities against carbapenem-resistantresistant Pseudomonas aeruginosa (CP-PA), carbapenem-resistantresistant Klebsiella pneumoniae (CP-KP), cephalosporin-resistant Clostridium difficile (CR-CD), macrolide- resistantresistant Streptococcus pyogenes (MR-SP), Voriconazole-resistant Aspergillus Niger (VR-AN) and Fluconazole-resistant Candida glabrata (FR-CG). Physico-chemical parameters were done by Medchem Designer^TM software version 5.5 and ADMET parameters by pkCSM online tool. Furthermore, molecular docking was accomplished with PyRx 0.8 by AutoDock Vina program. Results: All the synthesized derivatives were characterized and evaluated for their anti-bacterial activity, which shows the significant activity of 6i with MIC 36.17 μM on CP-PA, MIC 36.86 μM on CP-KP, MIC 38.45 μM on CR-CD, and MIC 37.09 μM on MR-SP, with respect to ciprofloxacin with an average of MIC 32 μM for all resistant bacterial strains. The prototype derivatives were also evaluated for their anti-fungal activity, in which derivative 6i was found to be significant with MIC 35.27 μM for VR-AN, MIC 34.78 μM for FR-CG, and MIC values of 25.60 μM and 27.08 μM for Nystatin for all fungal-resistant strains. In-silico predicted parameters for synthesized prototype derivatives stood to be drug-like. Conclusion: From the novel benzothiazole and pyrazole hybrid derivatives, compound 6i was found to be effective for anti-microbial and anti-fungal drugs and hence can be further explored for dual activities. Furthermore, derivatization was made to synthesize further potent derivatives for anti-microbial and anti-fungal treatments.

Background: Pyroglutamic acid is one of the cheapest chiral synthon for the synthesis of a variety of bioactive molecules ranging from synthetic to natural origin. Derived from glutamic acid by internal cyclization pyroglutamic acid can serve easily as a precursor for prolines or pyroglutaminols by the selective reduction of lactam carbonyl or carboxylic group, respectively. Pyroglutamic acid has two differential carbonyls and a lactam NH group. All these can differentially be modified to get a variety of compounds. These applications coupled with the easy availability of pyroglutamic acid have made it a choice of interest for various research groups in recent years to get a range of bioactive compounds both of natural as well as synthetic origins. In our ongoing research programme, we were interested to develop an easy route for the synthesis of 5-substituted pyrrolidin-2-ones exploiting the chemistry of pyroglutamates, whose synthetic potential is well established. Objective: To develop a simple and efficient methodology for the synthesis of 5-sustituted- pyrrolidin-2-ones as bioactive molecules/intermediate to bioactive molecules. Methods: N-Benzyl-5(S)-pyroglutaminol 1, (0.96 g, 5.0 mmol) was taken in THF (15 mL) and diethylazodicarboxylate (DEAD) (1.21 g, 1.4 eq) and triphenylphosphine (Ph3P) (1.72 g, 1.4 eq), were added to it and the reaction mixture was stirred at RT for 30 min. After 30 min a solution of the substituted pyrazole/imidazole derivative (1.2 eq) in THF (10 mL) was added and the reaction mixture was stirred again at RT for 7 hr. The progress of the reaction was monitored by thin layer chromatography (TLC). At the completion of the reaction, the solvents were evaporated under a vacuum to give a liquid which was poured into water (15 mL) and extracted twice with ethyl acetate (2 x 20 mL). The combined organic layer was washed with brine solution (15 mL), dried over sodium sulfate, concentrated and purified by column chromatography on silica gel using 20% EtOAc-hexane as eluent to give pure compounds 2 a-d, 3 and 4, respectively in satisfactory yields. Results: Herein, we wish to describe the synthesis of new 5(S)-substituted pyrrolidin-2- one derivatives through Mitsunobu reaction of N-benzyl-5(S)- pyroglutaminol with substituted pyrazole and imidazole derivatives. Conclusion: An easy and straightforward approach towards the synthesis of enantiomerically pure N-benzyl- (S)-5-substituted pyrrolidin-2-ones from N-benzyl-5(S)- pyroglutaminol through Mitsunobu reaction has been developed. These N-benzyl-(S)-5-substituted pyrrolidin-2-ones could be useful for the synthesis of bioactive natural products requiring pyrazole/imidazole moiety attached at C-5 position of native pyrrolidin-2- one moiety.

Background: Plants continue to be widely used in Algeria to treat many health disorders; hence, there is a need to find new natural substances of plant origin with effective biological properties. Objective: The aim of this study was to investigate the bioactivity of two apiaceous species, Daucus gracilis and Carum montanum, growing in Algeria in order to find new uses of local plants that can replace expensive and inaccessible medicines by local people. Methods: The methanolic extracts (MEs) were prepared in water/methanol solvent. Afterwards, an estimation of total phenolic content (TPC) was made. The MEs were tested for their antimicrobial activities by the disc diffusion test; the antioxidant activity of the MEs alone and their combinations was tested using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) and the reducing power tests. The antihemolytic effect was tested by the stabilization of the human red blood cell (HRBC) membrane method, and the in vitro antiinflammatory activity was evaluated by the protein denaturation method. Results: The MEs were found to be high in TP with 149.05 μg/mg in D. gracilis and 101.50 μg/mg in C. montanum. The best antimicrobial activity recorded with B. cereus (9.5mm) was lower than that of gentamicin (GM: 10μg) at 19-20 mm. The MEs exhibited the highest antioxidant activity (IC50=60.09 μg/ml for D. gracilis, 65.04 μg/ml for C. montanum) and reducing power effect, which was strongly concentration-dependent. The extract of D. gracilis exhibited important membrane stabilization, and the inhibition of denaturation was directly related to the concentration; Carum extract was found to be active with an IC50 value of 298.12μg/ml and Daucus with an IC50 value of 554.07μg/ml. Conclusion: It can be concluded that these two species can be used for food preservation and in herbal medicine after additional toxicity and molecular characterization studies.

Background: P. aeruginosa, has been frequently connected to immune-compromised individuals. Dynamic electrochemical metabolite assists in the creation of biofilms, the production of genes, and the maintenance of bacterial cells. The bacteria produce several phenazine derivatives, as well as the blue-green pigment pyocyanin, which works as a signalling molecule in quorum signalling and virulence factors. Objective: This review paper intends to give information on the compound's history, virulence mechanism, current biological horizon opened, as well as antagonism and bio-control actions in other bacteria. Current industrial trends and the prospects of pyocyanin-based development were also analysed. Methods: A bibliographic search of scientific literature published up to 2020 was conducted using scientific databases and search engines. Pyocyanin, phenazine, Pseudomonas, virulence, quorum signalling, health, in vivo, and clinical investigations were among the keywords used in various combinations. The data were retrieved independently from eligible papers using the usual data extraction approach. Results: Due to pyocyanin's antibacterial properties, the pharmaceutical industry is predicted to grow faster than other businesses. P. aeruginosa which has had its respiratory chain altered by protonated 3,5-dichlorophenol in water can be used as a biosensor. Cellular systems exposed to the chemical experience increased oxidative stress, which leads to gradual apoptosis. Pyocyanin is engaged in bacterial signalling processes, influencing colony shape and alarming innate immune cells. Conclusion: Focused research on the virulence factor is required, as the specific contribution remains unknown. The link between biological and therapeutic features needed well description to determine the precise action mechanism(s) to design novel medications.

Background: In recent years, diabetes and its risk factors were linked to an augmented occurrence of cardiovascular diseases (CVD), which are considered major causes of morbidity and mortality in diabetes mellitus subjects. Hyperinsulinemia (HI) and hyperglycemia (HG) are recognized as insulin resistance-inducers, which can trigger several alterations in cellular biogenesis besides inflammatory signaling activation. As a folk medicine in many countries, Artemisia herbaalba has been preclinically studied for treatment of type 2 diabetes mellitus (T2DM) and showed beneficial effects on hyperglycemia. Methods: In the current work, we explored the potential mechanisms underlying the antihyperglycemic behavior of the ethanolic extract of A. herba-alba and its bioactive compounds. Results: Obtained data demonstrated that ethanolic extract of A. herba-alba enhances HepG2 viability and proliferation, decreases considerably the apoptosis, through the regulation of pro- and anti-apoptotic pathways implying p53, p21 and Bcl-2 genes expression and Pan caspases activation under IR concentration at the lowest concentrations. A. herba-alba extract treatment additionally exhibited a potential antioxidant effect, evidenced by the significant decrease in total intracellular reactive oxygen species (ROS) levels and the improved mitochondrial transmembrane potential in HG/HI-challenged HepG2 cells (p < 0.001). Furthermore, A. herba-alba positively upregulated Irs1 and Irs2 as well as Akt/Pi3K pathway compared to insulin-resistant untreated cells, and subsequently stimulated glucose uptake in response to insulin infusion, as a consequence of its signal transduction restoration. Conclusion: Overall, the obtained data highlighted the beneficial effects of A. herba-alba ethanolic extract in ameliorating insulin signaling and liver cells metabolic balance, and shed the light for its use as a promising and safe therapeutic lead for the management of type 2 diabetes and underlying metabolic failures.

Cancer is a prominent cause of death that places a significant financial strain on the healthcare system. Because of its prevalence, there is unquestionably unmet need for new chemotherapeutics. Atypical activation and deregulation of the wingless (Wnt) signaling pathway are considered one of the major causes of various types of carcinomas. This receptor activation is directly correlated with the activation of β -catenin and β-catenin-dependent transcription. In the modern era of drug development, natural compounds have shown to be an unrivaled source of anticancer medications. Herbal compounds have been identified as potent β-catenin signaling inhibitors, mainly by their downregulation, modulating its phosphorylation, increasing ubiquitination and proteasomal destruction, blocking nuclear translocation, or other molecular mechanisms. In vitro and in vivo studies have revealed that these natural product inhibitors can prevent and treat cancer in a variety of cancer models. Natural products have the potential to be promising novel molecules for cancer treatment, making them an essential topic of study. The importance of natural products in blocking the numerous signaling pathways that promote carcinogenesis is explored in this review, paving the way for developing and discovering anticancer medicines.