Multitarget Activity Research Articles

Potentiation of Antibiotic Activity of Aztreonam against Metallo-β-Lactamase-Producing Multidrug-Resistant Pseudomonas aeruginosa by 3-O-Substituted Difluoroquercetin Derivatives.

The combination of aztreonam (ATM) and ceftazidime-avibactam (CAZ-AVI; CZA) has shown therapeutic potential against serine-β-lactamase (SBL)- and metallo-β-lactamase (MBL)-producing Enterobacterales. However, the ability of CZA to restore the antibiotic activity of ATM is severely limited in MBL-producing multidrug-resistant (MDR) Pseudomonas aeruginosa strains because of the myriad of intrinsic and acquired resistance mechanisms associated with this pathogen. We reasoned that the simultaneous inhibition of multiple targets associated with multidrug resistance mechanisms may potentiate the antibiotic activity of ATM against MBL-producing P. aeruginosa. During a search for the multitarget inhibitors through a molecular docking study, we discovered that di-F-Q, the previously reported efflux pump inhibitor of MDR P. aeruginosa, binds to the active sites of the efflux pump (MexB), as well as various β-lactamases, and these sites are open to the 3-O-position of di-F-Q. The 3-O-substituted di-F-Q derivatives were thus synthesized and showed hereto unknown multitarget MDR inhibitory activity against various ATM-hydrolyzing β-lactamases (AmpC, KPC, and New Delhi metallo-β-lactamase (NDM)) and the efflux pump of P. aeruginosa, presumably by forming additional hydrophobic contacts with the targets. The multitarget MDR inhibitor 27 effectively potentiated the antimicrobial activity of ATM and reduced the MIC of ATM more than four-fold in 19 out of 21 MBL-producing P. aeruginosa clinical strains, including the NDM-producing strains which were highly resistant to various combinations of ATM with β-lactamase inhibitors and/or efflux pump inhibitors. Our findings suggest that the simultaneous inhibition of multiple MDR targets might provide new avenues for the discovery of safe and efficient MDR reversal agents which can be used in combination with ATM against MBL-producing MDR P. aeruginosa.

Phytocompounds-based therapeutic approach: Investigating curcumin and green tea extracts on MCF-7 breast cancer cell line

BackgroundBreast cancer (BC) has transcended lung cancer as the most common cancer in the world. Due to the disease's aggressiveness, rapid growth, and heterogeneity, it is crucial to investigate different therapeutic approaches for treatment. According to the World Health Organization (WHO), Plant-based therapeutics continue to be utilized as safe/non-toxic complementary or alternative treatments for cancer, even in developed countries, regardless of how cutting-edge conventional therapies are. Despite their low bioavailability, curcumin (CUR) and green tea (GT) represent safer therapeutic options. Due to their potent molecular-modulating properties on various cancer-related molecules and signaling pathways, they are considered gold-standard therapeutic agents and have been incorporated into the development of one or more therapeutic strategies of BC treatment. MethodsWe investigated the modulatory role of CUR and GT extracts on significant multi molecular targets in MCF-7 BC cell line to assess their potential as BC multi-targeting agents. We analyzed the phytocompounds in GT leaves using High-performance liquid chromatography (HPLC) and Gas chromatography-mass spectrometry (GC-MS) techniques. The mRNA expression levels of Raf-1, Telomerase, Tumor necrosis factor alpha (TNF-α) and Interleukin-8 (IL-8) genes in MCF-7 cells were quantified using quantitative real-time PCR (qRT-PCR). The cytotoxicity of the extracts was assessed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and the released Lactate dehydrogenase (LDH), a valuable marker for identifying the programmed necrosis (necroptosis). Additionally, the concentrations of the necroptosis-related proinflammatory cytokines (TNF-α and IL-8) were measured using enzyme-linked immunosorbent assay (ELISA). ResultsIn contrast to the GT, the results showed the anticancer and cytotoxic properties of CUR against MCF-7 cells, with a relatively higher level of released LDH. The CUR extract downregulated the oncogenic Raf-1, suppressed the Telomerase and upregulated the TNF-α and IL-8 genes. Results from the ELISA showed a notable increase in IL-8 and TNF-α cytokines levels after CUR treatment, which culminated after 72 h. ConclusionsAmong both extracts, only CUR effectively modulated the understudy molecular targets, achieving multi-targeting anticancer activity against MCF-7 cells. Moreover, the applied dosage significantly increased levels of the proinflammatory cytokines, which represent a component of the cytokines-targeting-based therapeutic strategy. However, further investigations are recommended to validate this therapeutic approach.

Efficacy and safety of aniseed powder for treating gastrointestinal symptoms of COVID-19: a randomized, placebo-controlled trial.

Background: Gastrointestinal symptoms are prevalent amongst patients with a confirmed diagnosis of COVID-19 and may be associated with an increased risk of disease severity. This trial aimed to evaluate the efficacy and safety of aniseed (Pimpinella anisum L.) powder as an add-on therapy to standard care for treating gastrointestinal symptoms experienced by adults with an acute SARS-CoV-2 infection. Methods: The study was a randomized parallel-group double-blinded placebo-controlled add-on therapy trial. Adults with an acute SARS-CoV-2 infection who did not require hospitalization and reported at least one gastrointestinal symptom in the preceding 48h were assigned to either the aniseed or placebo group in a 1:4 ratio. All 225 participants (45 in the aniseed group and 180 in the placebo group) were instructed to use 25g of powdered aniseed or placebo twice daily for 2weeks. The primary outcomes were the proportion of patients who experienced an improvement of at least one point in the symptom score after adjusting for age group, gender, and time. Backwards stepwise logistic regression was applied to calculate the risk ratios. The clinical symptoms and adverse events were assessed at the beginning, 1week later, and at the end of the trial (week two). Results: Participants in the aniseed group were significantly more likely to report symptom improvement for abdominal pain [adjusted risk ratio (RR):0.55; 95% confidence interval (CI): 0.46-0.72], anorexia (RR:0.62; 95% CI: 0.47-0.82), and diarrhea (RR:0.19; 95% CI: 0.12-0.30), but not nausea/vomiting (RR:0.87; 95% CI: 0.71-1.08) or bloating (RR:0.87; 95% CI: 0.72-1.05). Two participants in the aniseed group and three participants in the placebo group reported mild to moderate adverse events. Conclusion: This study showed that 2weeks of aniseed powder containing trans-anethole (87%-94%) may help improve abdominal pain, anorexia, and diarrhea in COVID-19 patients. The findings align with the known biological, multitargeted activity of P. anisum and trans-anethole, which includes inhibiting SARS-CoV-2 along with other anti-infective, anti-inflammatory, antioxidant, hepatoprotective, and anti-dysbiosis properties. Multicenter trials with larger sample sizes and longer follow-up are warranted to confirm these findings. Clinical Trial Registration: Iranian Registry of Clinical Trials (IRCT20120506009651N3).

Systematic identification and characterization of compounds with reliable activity against multiple target proteins from different classes

Polypharmacology provides a basis for the treatment of diseases originating from perturbed target and pathway networks. It depends on the use of compounds with suitable multi-target activity and pharmacological effects resulting from multi-target engagement. In addition to their central role for polypharmacology, multi-target compounds are also of interest for basic research, for example, to better understand their binding characteristics or interaction patterns. While it is not unlikely that active compounds might bind to closely related targets, we have been interested in identifying compounds that are active against distantly or unrelated proteins, representing more unexpected instances of multi-target activity. Therefore, we have carried out a systematic search for compounds with activity against proteins from different classes, termed multi-class compounds (MC-CPDs). To this end, currently available compound activity data from medicinal chemistry were carefully curated. Subsequent analysis of ∼120,000 qualifying compounds with high-confidence target annotations identified 689 MC-CPDs with activity against at least three targets from two different protein classes. The target distribution of these compounds was determined and structural relationships were explored together with activity profiles. MC-CPDs covered many target combinations and established a wealth of compound-based target relationships, some of which could be rationalized by considering ligand binding characteristics of distinct targets. As a part of our study, the collection of newly identified MC-CPDs and associated target information is made publicly available.

In silico screening and identification of lead molecules from Garcinia gummi-gutta with multitarget activity against SARS-CoV-2

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19, has affected the human population, resulting in multiple waves of pandemics around the world. One of the main threats is hyper-evolved viral variants with high transmissibility and virulence, and the best solution is the application of multitargeted drugs of plant origin. In this perspective, the anti-SARS-CoV-2 activity of Garcinia gummi-gutta was evaluated through an in silico approach. A total of 97 phytochemicals from G. gummi-gutta were tested against three therapeutic targets of SARS-CoV-2, namely spike protein, main protease (Mpro), RNA-dependent RNA polymerase, and two human host targets such as angiotensin-converting enzyme-2 and nuclear factor-κB through molecular docking. Out of 97 phytochemicals screened, 18 of them showed significant binding free energy with all the five selected targets. The compound amentoflavone was chosen as the best lead molecule based on binding energy, molecular interactions, and absorption distribution metabolism and excretion profile. The interaction of amentoflavone with Mpro was further verified using molecular dynamic simulation. The overall results revealed that the compound amentoflavone can be recommended as the best lead compound with multitargeting potential against SARS-CoV-2, and can be recommended for further experimental studies leading to drug discovery.

Aminoguanidine Hydrazone Derivatives: The Antioxidant, Antineoplastic Profile, and Interaction with ctDNA Studies

Herein, we report the synthesis and evaluation of four aminoguanidine hydrazone derivatives with different aromatic moieties. This class of compounds presents a series of biological applications. Derivative AGH-3 with an indole nucleus offered the highest antioxidant capacity with results comparable to Trolox in 2,2-diphenyl-2-picrylhydrazyl radical (DPPH• ), 2,2-azinobis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS•+), FeIII reduction assay (FRAP), and nitric oxide (•NO) radical scavenging assays. Furthermore, AGH-3 showed the highest antiproliferative activity against human kidney cancer cells (786-0) with concentration necessary to inhibit 50% cell growth (GI50) = 6.3 µM; additionally, in biophysical studies, AGH-3 interacted with ctDNA (biological target model) forming a fluorescent supramolecular complex with a binding constant (Kb) of 2.89 × 103 M-1 with preferentially an intercalator mechanism. The tested compounds revealed the potential of aminoguanidine hydrazones as a strategic class of compounds with multitarget biological activity.

Single crystal X-ray, DFT, molecular dynamic simulations, and biological evaluation of 3-OH pyrrolidine derivative VA10 from alkaloid vasicine for BACE1 inhibition

Alzheimer's is a progressive neurodegenerative disease with amyloid-beta peptide deposition that impairs memory and cognitive decline. Due to lack of effective treatment for Alzheimer's disease (AD), there is an interest in finding novel compounds to treat AD. The alkaloid vasicine derivative VA10 inhibited cholinesterases and amyloid beta aggregation in Alzheimer induced rats and showed multi-target activity in treating AD. Therefore, the present study uses single-crystal X-ray and DFT studies to evaluate the properties of VA10′s physicochemical properties, reactivity, and stability. Further, the scaffold VA10 was assessed through in silico, in vitro BACE1 inhibition, and in vivo CNS toxicity experiments. The VA10 Hirshfeld surface analysis and fingerprint plots were determined to understand intra and intermolecular interactions. Furthermore, HOMO-LUMO, UV, and IR studies investigated the electrical and vibrational characteristics. The molecular docking and molecular dynamics simulation studies revealed that compound VA10 formed key interactions with active site amino acid residues and well resided at the BACE1 active site. The VA10 was found to be a potent BACE1 inhibitor and showed no sign of toxicity in rats up to 50 mg/kg. The study identifies VA10, a vasicine derivative, as a possible BACE1 inhibitor in treating Alzheimer's disease. Furthermore, comparing experimental and theoretical results may be beneficial in evaluating VA10′s molecular interactions and reactivity.

Exploration of multitargeted antialzheimer's activity of safflower leaves phytoconstituents: In silico molecular docking approach

The plants on earth are a blessing to both humans and animals. Both humans and animals depend on them, to survive in many ways. The plants help us in meeting our food demands while also aiding the treatment of numerous illnesses like alzheimer, cancer, asthma, and others. Among the numerous plants, the safflower leaves are used as vegetables in India and many Asian countries. Along with veggies, safflower leaves have a variety of health benefits for treating ailments. In this regard, the major goal of this study was to examine the multitargeted anti-alzheimer's activity of eight phytoconstituents identified in safflower leaves. Molecular docking study has been performed on each of the eight molecules with the targets linked to alzheimer's disease. The compounds were docked with beta-secretase 1, beta-secretase 2, and butyrylcholinesterase by using the autodock vina algorithm inbuilt in the PyRx software. Four FDA-approved drugs were selected for the comparative analysis along with these eight compounds. The analysis showed that almost all compounds have stronger affinity for the selected targets than FDA-approved drugs. Finally, Quercetin-7-O-(6"-O-acetyl)-β-d-glucopyranoside was selected as best based on binding energy (−8.4 to −10.2) and the interactions for all the selected targets. The toxicity analysis was also performed for best bioactive and FDA-approved drug. Finally, molecular dynamics analysis was performed to analyse the complexes stability. Overall, this study will help the scientific community and society to find a novel drug candidate for the treatment of Alzheimer's disease.

Evaluation of F3S4-m loaded liposomes as anti-AChE and its cytotoxic activity in PC12 and HMC3 cells

The current research discusses the loaded of F3S4-m compound reported with multitarget activity acting as an inhibitor of acetylcholinesterase (AChE), beta-secretase 1 (BACE1), and amyloid beta (Aβ) aggregation. Despite great effort has been done to have a compound to treat Alzheimer’s disease (AD) and not only its symptomatology, nowadays there is not an effective compound in the market yet. Several synthetized compounds reported having a good activity in vitro study turned out not having it in vivo, it is believed that many of them are not able to reach the brain due to low biodisponibility, besides many of them have charged chemicals groups or tertiary amines, which have been substrates of deaminases enzymes. Therefore, the use of liposomes results an interesting strategy to deliver this kind of compounds to the brain. Then in this work it is proposed the use flexible liposomes made from phosphatidylcholine (PC) and cholesterol (Chol) to encapsulate the F3S4-m compound and evaluate its inhibitory activity against AChE. The results showed that empty liposomes particle size is influenced by the content of cholesterol in their membranes being larger for those containing 20% of cholesterol than those with 10%. The toxicity of F3S4-m loaded liposomes in PC12 cells was also evaluated employing the 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay (MTT). The results showed that F3S4-m loaded liposomes can inhibit the enzymatic activity of AChE, but the concentration of encapsulated F3S4-m needed to inhibit AChE was 2-times higher than what was previously reported in solution.Graphical abstract

Mulberry leaf multi-components exert hypoglycemic effects through regulation of the PI-3K/Akt insulin signaling pathway in type 2 diabetic rats

Ethnopharmacological relevancePhytochemicals have unique advantages in the treatment of diabetes due to their multi-target activity and low toxicity. Mulberry leaves, a traditional Chinese herbal medicine, have been used in the prevention and treatment of diabetes for centuries. The main active ingredients in mulberry leaves with regards to the hypoglycemic effect are 1-deoxynojirimycin, flavonoids, and polysaccharides. However, the combined hypoglycemic effects and mechanisms of mulberry leaf multi-components remain unclear. Aim of the studyThis study explored the anti-diabetic effects of mulberry leaf multi-components (MMC) and the role of the PI-3K/Akt insulin signalling pathway in improving insulin resistance. Materials and methodsThe main chemical components of MMC were analyzed using the phenol-sulfuric acid method, aluminum nitrate-sodium nitrite method, and HPLC-ultraviolet/fluorescence detection method. The T2DM rat model was created via feeding a high-fat diet and peritoneal injection of streptozotocin. T2DM rats were divided into four groups: model, model plus metformin, model plus low-dose, and model plus high-dose MMC groups (100 and 200 mg/kg body weight/day, respectively), and plus normal group for a total of five groups. MMC was administered by oral gavage for six weeks. Fasting blood glucose and serum lipid profiles were measured using a glucometer and an automatic biochemistry analyzer, respectively. Serum insulin and adipocytokine levels were analyzed by ELISA. Hepatic glucose metabolizing enzyme activity was evaluated by ELISA and the double antibody sandwich method. Expression of PI-3K/Akt signalling pathway proteins was analyzed by RT-PCR and Western blotting. ResultsExtracted 1-deoxynojirimycin, flavonoid, and polysaccharide purity was 70.40%, 52.34%, and 32.60%, respectively. These components were then mixed at a ratio of 1:6:8 to form MMC. MMC significantly reduced serum glucose, insulin, and lipid levels. In diabetic rats, MMC enhanced insulin sensitivity and alleviated inflammatory and oxidative damage by lowing adipocytokine levels and increasing anti-oxidative enzyme activity. Insulin resistance was also mitigated. MMC regulated the activity of key downstream enzymes of hepatic glucose metabolism via activating the expression of PI-3K, Akt, PDX-1, and GLUT4 at the mRNA and protein levels, thereby correcting hepatic glucolipid metabolism disorders and exerting a hypoglycemic effect. ConclusionMMC ameliorated hepatic glucolipid metabolism disorders and improved insulin resistance in T2DM rats by activating the PI-3K/Akt signaling pathway. These results highlight the multi-component, multi-target, and combined effects of MMC, and suggest it may be further developed as a hypoglycemic drug.

Research Progress and Future Development Potential of Oridonin in Pharmacological Activities.

In recent years, attention has increasingly focused on herbal medicines and their bioactive components attributed to their multi-target pharmacological activity and low side effects. Oridonin is a natural diterpenoid extracted from the traditional Chinese herb and is one of the main active components of Rabdosia rubescens. Modern pharmacological studies have shown that oridonin has anti-tumor, anti-bacterial, anti-inflammatory, anti-oxidant, cardiovascular protective, immunomodulatory, and other effects. Based on the published literature in recent years, we outline the pharmacological activities of oridonin, aiming to provide a theoretical basis for the design and development of new oridonin-based drugs, as well as to facilitate the process of oridonin for clinical use.

Diallyl Trisulfide Causes Male Infertility with Oligoasthenoteratospermia in Sitotroga cerealella through the Ubiquitin-Proteasome Pathway.

Essential oils extracted from plant sources along with their biologically active components may have negative effects on insects. Diallyl trisulfide (DAT) is an active component of garlic essential oil, and it exhibits multi-targeted activity against many organisms. Previously we reported that DAT induces male infertility and leads to apyrene and eupyrene sperm dysfunction in Sitotroga cerealella. In this study, we conducted an analysis of testis-specific RNA-Seq data and identified 449 downregulated genes and 60 upregulated genes in the DAT group compared to the control group. The downregulated genes were significantly enriched in the ubiquitin-proteasome pathway. Furthermore, DAT caused a significant reduction in mRNA expression of proteasome regulatory subunit particles required for ATP-dependent degradation of ubiquitinated proteins as well as decreased the expression profile of proteasome core particles, including β1, β2, and β5. Sperm physiological analysis showed that DAT decreased the chymotrypsin-like activity of the 20S proteasome and formed aggresomes in spermatozoa. Overall, our findings suggest that DAT impairs the testis proteasome, ultimately causing male infertility characterized by oligoasthenoteratospermia due to disruption in sperm proteasome assembly in S. cerealella.

New 2-alkoxycyanopyridine derivatives as inhibitors of EGFR, HER2, and DHFR: Synthesis, anticancer evaluation, and molecular modeling studies

New series of substituted 2-alkoxycyanopyridine derivatives were synthesized and evaluated for their in vitro and in vivo anticancer activities. Comparing the evaluated activities against cancer cell lines to the broad-spectrum anticancer doxorubicin, and the kinase inhibitor sorafenib, compounds 3a, 4b, 4c, 7a, and 8d demonstrated superior anticancer efficacy with elevated safety profiles and selectivity indices, particularly against MCF7 breast cancer. For exploration of their mechanism of action, assays for inhibition of EGFR, HER2 kinase, and DHFR were performed. The promising synthesized compounds exhibited potent dual kinase EGFR/HER2 inhibitory activity with IC50values of 0.248/0.156 μM for 4b and 0.138/0.092 μM for 4c. Additionally, with IC50 values of 0.138 and 0.193 M, respectively, 4b and 4c had the greatest DHFR inhibitory activity that was comparable to methotrexate. In the MCF7 breast cancer cell line, they caused arrest at the S phase of the cell cycle and exhibited apoptosis induction activity. With restored caspase-3 immunoexpression, the anti-breast cancer assay performed in vivo of 4b and 4c demonstrated a substantial decrease in tumor volume. Results from molecular modeling were in agreement with biological assays proving the importance of the 3-caynopyridine, two substituted phenyl rings attached to central pyridine ring, and propoxy side chain moieties for binding with the receptors. As 4c works by inhibiting both EGFR/HER2 kinase, DHFR enzymes, in addition to cellular apoptosis, it could be viewed as a model of compounds possessing a multi-targeting anticancer activity. Collectively, compounds 4b and 4c might represent prototypes for further development as anticancer molecules.

Network pharmacology on mechanistic role of Thymus linearis Benth. against gastrointestinal and neurological diseases

BackgroundThymus linearis Benth. (TL) is native to the Himalayas and has been used traditionally to cure various diseases. Thymus is a well-known aromatic perennial herb commonly known as Van ajwain or Himalayan Thyme. The main components of the TL essential oil are thymol, terpinene, and p-cymene. There are many biological properties that TL has been reported to exhibit, including antioxidant, analgesic, anti-inflammatory, antipyretic, antibacterial, anticancerogenic, and neuroprotective effects. PurposeIn this study, the network pharmacology and molecular docking were used to explore the potential compounds of TL and their interaction mechanism toward gastrointestinal complications and neurological diseases. MethodsNetwork pharmacology was used to analyze the active compounds and protein targets of TL on gastrointestinal and neurological related diseases. Protein-protein interaction and Kyoto Encyclopaedia of Genes and Genomes analysis were used to enrich and evaluate key pathways of target proteins. To ensure the reliability of the network pharmacology prediction estimates, molecular docking was used to confirm the relationships between the core components and targets of TL. Result77 physiologically active compounds and their 717 predicted protein targets with high association to the neuroactive ligand-receptor interaction pathway were derived from TL. Beta-citronellol, piperitol, p-cymen-8-ol, and alpha-humulene were found to have a role in gastrointestinal diseases associated with neurological diseases. These compounds showed significant levels of multitargeting cluster regulatory activity. The molecular docking results showed regulatory activity of highlighted multi-targeting compounds and the highest docking energy was reported in piperitol. ConclusionThe study shows that Thymus linearis Benth., a medicinal plant with traditional use, possesses valuable biologically active compounds. It emphasizes the potential of Thymus in treating gastrointestinal and neurological diseases by regulating oxidative stress pathways. This research opens up possibilities for discovering antioxidant molecules for future drug development. It is an interesting study with promising implications for further research.

The Importance of the Piperazine Ring for the Development of Trypanomicide Compounds

AbstractChagas disease (CD) is one of extremely Neglected Tropical Diseases (NTD) that have been challenging the health of billions of people in the world. Despite being a threat worldwide many of these diseases have a scarce chemotherapeutic armamentarium and the drugs currently used are not effective because of several reason, such as drug resistance, serious side‐effects, among others. Only two drugs are currently available for CD therapeutics, and they are not active in the chronic phase of the diseases. Considering the huge necessity of drugs for this parasitosis, the search for either new or better drugs than those used, many research groups have been involved in this investigation. New scaffolds can be used with this purpose and piperazine is one of them. Since it has many chemical, pharmacological and pharmacokinetics advantages, including multitarget activity, this group has been often used in CD. In this review, which the role of piperazine group in the structure‐activity of some important targets for T. cruzi, as cruzain, trypanothione reductase, Fe‐superoxide dismutase, and nitroreductase as well, is comprehended, several examples have been given to inspire researchers to optimize either hit or lead compounds against T. cruzi.

Review of the Biological Activity of Rutin: Antidiabetic, Antioxidant, Anti-inflammatory and Antitumor

Various parts of plants have long been widely used for the treatment and prevention of diseases. They are a valuable source of biologically active compounds, especially they are rich in polyphenolic structures. Rutin belongs to the group of some of the most common flavonoids in plant objects. Animal organisms do not have enzyme systems for its synthesis, so it enters the human body only with plant food. Rutin is widely used as a component in herbal medicines, multivitamin preparations, in the cosmetology, food and chemical industries. This article discusses the biological activity of rutin, namely antidiabetic, antioxidant, anti-inflammatory and antitumor activity. The article summarizes the current data on the above-mentioned types of biological activity. It follows from the presented research results that rutin is a promising compound with multi-target activity for the treatment of various diseases. It can serve as a basis for the creation of new highly effective pharmacological molecules based on it.

Retraction Note: Polyphenols from Conyza dioscoridis (L.) ameliorate Alzheimer’s disease- like alterations through multi-targeting activities in two animal models

Retraction Note: Polyphenols from Conyza dioscoridis (L.) ameliorate Alzheimer’s disease- like alterations through multi-targeting activities in two animal models

In vitro multitarget activity of sulfadiazine substituted triazenes as antimicrobial, cytotoxic, and larvicidal agents.

Multidrug resistance (MDR) causes difficulties in the treatment of infections and cancer. Research and development studies have become increasingly important for the strategy of preventing MDR. There is a need for new multitarget drug research and advancement to reduce the development of drug resistance in drug-drug interactions and reduce cost and toxic effects. This study aimed to determine the effects of multi-target triazene compounds on antibacterial, antifungal, antiviral, cytotoxic, and larvicidal activities were investigated in vitro. A series of 12 novel of 1,3-diaryltriazene-substituted sulfadiazine (SDZ) derivatives were synthesized, and the obtained pure products characterized in detail by spectroscopic and analytic methods (FT-IR, 1 H-NMR, 13 C-NMR, and melting points). The antibacterial and antifungal activities of these derivatives (AH1-12) were determined by broth microdilution method. All derivatives have been evaluated in cell-based assays for cytotoxic and antiviral activities against Modified Vaccinia Virus Ankara. The larvicidal efficacy of these chemical compounds was also investigated by using Lucilia sericata (L. sericata) larvae. Twelve 1,3-diaryltriazene-substituted SDZ derivatives (AH1-12) were designed and developed as potent multitargeted compounds. Among them, the AH1 derivative showed the most antibacterial and antifungal activity. Besides, synthesized derivatives AH2, AH3, AH5, and AH7 showed higher antiviral activity than SDZ. All synthesized derivatives showed higher cytotoxic activity than SDZ. Also, they showed larvicidal activity at 72 h of the experiment. As a result, these compounds might be great leads for the development of next-generation multitargeted agents.

Pharmacological Potential of Betulin as a Multitarget Compound.

Betulin is a natural triterpene, usually from birch bark, known for its potential wound-healing properties. Despite having a wide range of pharmacological targets, no studies have proposed betulin as a multitarget compound. Betulin has protective effects against cardiovascular and liver diseases, cancer, diabetes, oxidative stress, and inflammation. It reduces postprandial hyperglycemia by inhibiting α-amylase and α-glucosidase activity, combats tumor cells by inducing apoptosis and inhibiting metastatic proteins, and modulates chronic inflammation by blocking the expression of proinflammatory cytokines via modulation of the NFκB and MAPKs pathways. Given its potential to influence diverse biological networks with high target specificity, it can be hypothesized that betulin may eventually become a new lead for drug development because it can modify a variety of pharmacological targets. The summarized research revealed that the diverse beneficial effects of betulin in various diseases can be attributed, at least in part, to its multitarget anti-inflammatory activity. This review focuses on the natural sources, pharmacokinetics, pharmacological activity of betulin, and the multi-target effects of betulin on signaling pathways such as MAPK, NF-κB, and Nrf2, which are important regulators of the response to oxidative stress and inflammation in the body.

Benzimidazole-derived carbohydrazones as dual monoamine oxidases and acetylcholinesterase inhibitors: design, synthesis, and evaluation

A series of novel benzimidazole-derived carbohydrazones was designed, synthesized and evaluated for their dual inhibition potential against monoamine oxidases (MAOs) and acetylcholinesterase (AChE) using multitarget-directed ligand approach (MTDL). The investigated compounds have exhibited moderate to excellent in vitro MAOs/AChE inhibitory activity at micromolar to nanomolar concentrations. Compound 12, 2-(1H-Benzo[d]imidazol-1-yl)-N'-[1-(4-hydroxyphenyl) ethylidene]acetohydrazide has emerged as a lead dual MAO-AChE inhibitor by exhibiting superior multi-target activity profile against MAO-A (IC50 = 0.067 ± 0.018 µM), MAO-B (IC50 = 0.029 ± 0.005 µM) and AChE (IC50 = 1.37 ± 0.026 µM). SAR studies suggest that the site A (hydrophobic ring) and site C (semicarbazone linker) modifications attempted on the semicarbazone-based MTDL resulted in a significant enhancement in the MAO-A/B inhibitory potential and a drastic decrease in the AChE inhibitory activity. Further, molecular docking and dynamics simulation experiments disclosed the possible molecular interactions of inhibitors inside the active site of respective enzymes. Also, computational prediction of drug-likeness and ADME parameters of test compounds revealed their drug-like characteristics. Communicated by Ramaswamy H. Sarma