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Abstract: ATP dependent MurC-F ligases are essential for the biosynthesis of peptidoglycan, an essential bacterial cell wall component that is required for bacterial cell survival. Last, in the series, MurF catalyzes the ATP-dependent addition of D-Ala-D-Ala dipeptide to UDP-N-acetylmuramyl-tripeptide to form the UDP-N-acetylmuramy-pentapeptide monomeric precursor of peptidoglycan. Owing to its critical essentiality in peptidoglycan biosynthesis and absence in eukaryotic counterparts, MurF is considered a promising target for the design and development of potent antibacterial agents. Several MurF inhibitors have been designed and evaluated for their MurF inhibitory and antibacterial activity. These include aminoalkylphosphinates, sulfonamides, diarylquinolones, hydroxylamines, phosphorylated hydroxylamines, thiazolylaminopyrimidines, 2,4,6-trisubstituted 1,3,5-triazines, etc. However, most of the inhibitors developed till date lack potent antibacterial activity against both Gram-positive and Gram-negative bacteria. In the present review, an updated status of MurF ligase inhibitors is presented that may provide a useful source for the design of novel MurF inhibitors with potent and broad-spectrum antibacterial activity.

Background: Sustained release of synthetic polymeric microparticles has gained more attention as drug delivery carriers because of their properties such as good stability, low toxicity, dosing frequency, and simple and mild preparation method. The present work was envisaged to reduce the dosing frequency by preparing drug loaded biodegradable microspheres by the O/O emulsion solvent evaporation technique. Objective: The objective behind microspheres’ preparation is to sustain the metformin release by using ethyl cellulose as a synthetic polymer. The model drug metformin having a low biological half-life (1.5-3 hours) is selected. Method: As the metformin is highly water soluble in nature, the oil-in-oil solvent evaporation techniques are used and span 80 is utilized as surfactant. The effect of stirring rate and surfactant concentration on the characteristics of encapsulation efficiency and drug release from the microsphere are investigated. Results: The results show that the drug-polymer (1:1) ratio gives better sustained release results. The obtained microparticles are characterized by X-RD analysis and Fe-SEM, and release behavior is checked for release patterns. A 32 full factorial design is employed for the responses. The free-flowing spherical microspheres show high drug entrapment efficiency. Conclusion: The data obtained suggest that microspheres can be successfully designed with sustained release for diabetic treatment.

Background: Curcumin, a polyphenolic compound present in the turmeric plant (Curcuma longa) is well known for its anti-aging, anti-tumor, anti-inflammatory, anti-mutagenic and antioxidative properties due to which turmeric has been used as a medicinal plant from ages. Objective: Our current study aims at finding the most potent targets of curcumin displaying efficient binding by using various systems biology tools. Around 560 genes related to wound healing are extracted from PubMed using the combination of words like wound healing, curcumin, Homo sapiens, etc. Methods: For the investigation of the mechanism of curcumin interference at the system level, proteinprotein interaction network (PPIN) of the proteins involved in the wound healing process was generated using the STRING database. The noise of the data generated in PPIN was removed by modulation of the network with the help of Molecular Complex Detection (MCODE) and finding the seed proteins. GO enrichment analysis along with network topology analysis and molecular docking will help in pinpointing the most important and efficient curcumin binding proteins. Results: The findings of this study shows that besides SCR, PPARG and MAPK3, AKT3 is one of the novel targets for wound healing as the binding affinity of AKT3 is -4.53 Kcal/mol, which is close to SRC with the highest binding affinity with binding energy of -6.6 Kcal/mol. The binding energy of PPARG was -6.2 Kcal/mol and for MAPK3 the binding energy was -5.95 Kcal/mol. Besides AKT3, FLT4 and RPS6KB1 were also the novel targets of curcumin with binding affinities of -4.13 Kcal/mol and -4.04 Kcal/mol. In network analysis, we obtained PIK3R1 as a connector node which acted as a hub node with highest betweenness score. Conclusion: From the results obtained, we can say that curcumin finds its role in all four stages of wound healing and it also prevents the healing cells from turning into tumors.

Background: Diabetic neuropathic pain seriously affects the quality of a patient’s life. To predict molecular mechanism based on network pharmacology and verify the interaction between the active ingredient of Astragalus membranaceus and Panax notoginseng coupled-herbs (AP) and target genes related to Diabetic neuropathic pain (DNP) molecular docking assay was performed. AP and their target genes related to DNP were analyzed based on network pharmacology followed by experimental validation. Methods: TCMSP, PubMed and CNKI websites were used to acquire active components in AP. OMIM, DrugBank database and DisGeNET database were used to collect and analyze target genes related to DNP. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and gene ontology (GO) analysis were conducted in the DAVID database. The protein-protein interaction (PPI) network model was constructed by introducing the selected components-disease common target into the string database. Auto- Dock Vina 1.1.2 was used to dock receptor proteins with small ligand molecules. VonFrey’s statement was used to detect mechanical allodynia of DNP rats. Potential targets were detected by Western blot assay. Results: We decided that 22 and 9 chemical compositions possessed the fair ability of absorption, distribution, metabolism and excretion in Astragalus membranaceus and Panax notoginseng, respectively. These active compositions act on 70 target genes related to DNP. The core gene in the protein-protein interaction network are CAT, ESR1, HMOX1, IL1β, IL6, NFE2L2, NOS2, PPARG, PTGS2 and TNF, etc. Furthermore, GO, and KEGG pathway enrichment analyses indicated that DNP related target genes regulated by AP exist in multiple signaling pathways, including insulin resistance, PI3K-Akt signaling, HIF-1 signaling pathway, Fluid shear stress and atherosclerosis, and AGE-RAGE signaling pathway etc. AP inhibited mechanical hyperalgesia and reduced SERPINE1, FN1, IL1β, and IL6 expression of diabetic neuropathic rats in a dose-dependent manner. Conclusion: We first confirm that AP possess an anti-DNP effect through multiple signaling pathways based on network pharmacology. These results provide a theoretical basis for us to further research on the molecular mechanism of AP in the treatment of DNP.

Abstract: The review aims to summarize the major and dominant natural antioxidants and their resources from medicinal and herbal plants with antiviral, anti-inflammation and antimicrobial activities. For this review manuscript, online databases, including Web of Science, Scopus, PubMed, and Science Direct, were searched for papers published from 1960 to November, 2021. Search terms consisted of “medicinal plants”, “traditional Iranian medicine”, “traditional Persian medicine”, “pharmaceutical properties”, “antioxidant activity”, “antiviral activity”, “anti-inflammation”, “antimicrobial” and “antibacterial activities”. (-)-Epicatechin, Caffeic acid, Gallic acid, Hydroxytyrosol, Kaempferol, and Resveratrol are some of the most important chemical compounds with antioxidant properties. Rosmarinic acid, Caffeic acid, Carnosol, P-Coumaric acid, Carnosic acid, Luteolin, Apigenin, and Kaempferol are the major chemical compounds with antiviral properties. Curcumin, Colchicine, Resveratrol, Capsaicin, (-)-Epigallocatechin, Quercetin, Myristicin, and Elmicin are the principal chemical compounds with anti-inflammatory properties. Isoeugenol, Coumarin, Piperonal, Scoparone, Spathulenol, D-Limonene, and Myrcene are the principal chemical compounds with antibacterial properties in traditional Iranian medicine. Persian traditional medicine, or Iranian traditional medicine, is one of the main ancient forms of traditional medicine, which has influenced knowledge regarding other medicinal plants in various countries. It has also been considered one of the most well-known traditional and holistic systems of medicine.

Background: Inhibition of cholinesterase enzyme has been recognized as an important target in the symptomatic treatment of Alzheimer’s disease. Objective: In the current work, a series of new N-(4-(imidazo[1,2-a]pyridin-2-yl)phenyl)cinnamamide derivatives were synthesized and their inhibitory activities against acetyl cholinesterase, butrylcholines terase, and Lipoxygenase were evaluated. Methods: The target compounds were synthesized as the literature reported with some modifications. The AChE, BChE, and LOX inhibitory activities of the synthesized compounds were evaluated using in vitro methods. The docking and kinetic studies were performed for the most potent compounds to evaluate the inhibition mechanism. Results: The structural elucidation of the synthesized imidazo-pyridine derivatives was performed by different spectroscopic techniques including IR, NMR, and Mass. Most of the synthesized compounds demonstrated good AChE, BChE, and LOX inhibitory activities. The most active AChE, BChE, and sLOX-1 inhibitors were found for compounds 4a, 4g, and 4l, respectively. The docking study also revealed that the three compounds, 4a, 4g, and 4l, have important binding interactions with the AChE, BChE, and sLOX-1 enzyme active sites, respectively. Conclusion: The results of current study shows imidazo[1,2-a]pyridine derivatives have potential for development of novel drug candidate for AD as AChE, BChE and sLOX-1 inhibitors.

Background: A large scale experimental validation conducted at the National Center for Advancing Translational Sciences (NCATS/NIH, USA) confirmed the predictions of our 3D-SDAR model of hERG blockage and phospholipidosis induction. It was demonstrated that both hERG blockage and phospholipidosis induction are driven by a common three-center toxicophore composed of two aromatic rings and an amino group. This work extends our earlier efforts by predicting the hERG blocking potential of pharmaceuticals from two additional datasets: i) one comprised of 106 drugs with reported clinical signs of cardiotoxicity from the AZCERT database and ii) a dataset of 54 FDA-approved tyrosine kinase inhibitors (TKIs). Methods: A bagging-like 3D-SDAR algorithm aggregating predictions from 100 randomized models was used to predict the hERG blocking potential of all 160 drugs. All 106 drugs from the AZCERT dataset were further evaluated for their hERG inhibition at NCATS using a thallium flux assay. Results: Comparison of the predicted hERG class against the results of the thallium flux qHTS assay resulted in an overall predictive accuracy of 0.736 and the area under the ROC curve of 0.780. Factors such as the generation of false negatives by the thallium flux assay, proximity to the cut-off, use of conformations that may differ from the biologically relevant ones, and the lack of structurally similar compounds in the modeling set could explain the somewhat reduced predictive performance compared to that of the original model. The original 3D-SDAR model was also used to evaluate the TKIs ability to block hERG. Comparing our predictions to class assignments based on IC50 values with a 30 μM cut-off, an accuracy of 0.850, sensitivity of 0.906, and specificity of 0.625 were achieved. Conclusion: 3D-SDAR provides a reliable platform for the prediction of hERG blockage. Particular attention should be paid to all investigational new drugs containing our three-center hERG toxicophore, especially those having highly flexible molecules. Particular scrutiny should be given to the tyrosine kinase inhibitors, which represent a therapeutic class possessing all structural characteristics previously associated with an increased potential to block hERG.

Background: Argan oil is one of the products used for antidiabetic purposes in Morocco. Objective: This work aims to study the acute and subchronic effect treatment of the roasted (Roil) and unroasted (UnRoil) Argan oils on oral glucose tolerance test (OGTT) and body weight in normal and diabetic rats, evaluate the effect of these oils on glucose absorption by the diaphragm and determine total polyphenol, flavonoids, tannins, chlorophyll and carotenoids amounts. Methods: The anti-hyperglycemic effect of Roil and UnRoil was investigated in normal and alloxanediabetic rats by treating the animals orally with 2 mLKg-1/day of oils for 1 day (Acute treatment) and 4 weeks (Subchronic treatment). Then, OGTT was carried out at the end of each treatment, and the body weight was checked for each week. Besides, these oils (1 gL-1) were tested on glucose absorption by the diaphragm isolated from Wistar rats in vitro. Results: This work shows that Roil and UnRoil significantly decrease the postprandial glycemic level in acute and subchronic treatments in normal and diabetic rats. Besides, the intake of these oils in diabetic rats significantly attenuates the postprandial glycemia compared to the acute-treated group. In vitro glucose uptake by the hemidiaphragm study shows that Argan oils promote glucose consumption by the muscles. Conclusion: Argan oils showed a very important anti-hyperglycemic effect, which could be explained by promoting peripheral glucose uptake. UnRoil shows a better effect than Roil on glucose consumption, meaning that the roasting process influences the phytoconstituent responsible for this activity.

Background: The COVID-19 outbreak is a serious concern and has caused a great loss to the global economy. Therefore, COVID-19 has become an urgent public health problem. Although new vaccines and small molecule drugs are now available, these prevention and treatment methods cannot completely control the epidemic due to the constant mutation of SARS-CoV-2. Targeting 3CLpro/RdRp is expected to develop drugs that are not susceptible to the mutation of SARS-COV-2, and it will also have a certain effect on the coronavirus that may appear in the future. Objective: This study aimed to find small molecules against SARS-CoV-2 with research potential and provide relevant data for the rational development of anti-SARS-COV-2 drugs. Methods: Targeting 3CLpro/RdRp, using Shards database (120,000 natural small molecule compounds) in the ZINC database, adopting a step-by-step screening strategy, and taking Lopinavir, Indinavir, and Molnupiravir as screening criteria was done. Moreover, the top scoring compounds were screened using rigid docking, and molecular dynamics simulation and ADME prediction were performed. Finally, the molecules with better scores were screened out. Results: After molecular docking with 3CLpro as the target, 3207 compounds meeting the screening criteria were obtained. After applying Lipinski's rule of five for drug property screening, 1825 compounds that met the criteria were obtained. After molecular docking with RdRp as the target, ZINC04259665 has a good docking score. According to molecular dynamics simulation results, ZINC04259665 is stable in combination with 3CLpro/RdRp. ADME prediction shows that ZINC04259665 has good druggability. Conclusion: Using 3CLpro/RdRp targets and then using a step-by-step strategy to screen the compound with the highest score through molecular dynamics simulation and ADME prediction, it was found that ZINC04259665 has good development potential and can be used as a follow-up hit compound for research. In addition, the data obtained provide relevant information for the rational development of anti- SARS-COV-2 drugs.

Background: Lycopene, a natural antioxidant from carotenoids, is produced by plants and microorganisms. It has been investigated in many studies in relation with potential health effects. Objective: Due to the high lipid-solubility of lycopene, its skin penetration is challenged. Therefore, in the present study, lycopene was loaded into lipid nanoparticles to improve penetration and pharmacological properties. Methods: Solid lipid nanoparticles (SLNs) containing lycopene were prepared and anti-tyrosinase properties were studied in the present study. The formulation was investigated in terms of drug release and antityrosinase properties. Determination of encapsulation efficiency was performed directly. Electron microscopy was used to examine the shape of the nanoparticles. Subsequently, the rate of drug release was investigated by the cell diffusion method. The present study applied cytotoxicity tests, cellular tyrosinase inhibition, melanin content, and free radical level to evaluate the effect of formulations on melanogenesis inhibition, and western blot assay was used to determine tyrosinase and MITF levels. Results: The results from particle size investigation for LYC-SLNs were 151.1 ± 2.3, and exploring the data of electron microscopy showed that the shapes of nanoparticles were spherical, and the encapsulation efficiency was 85.76 ± 2.75%. In determining the anti-tyrosinase effects of LYC-SLNs, a significant reduction in cellular tyrosinase activity and melanin and ROS levels were observed; It is also worth noting that LYC-SLNs reduced melanin production with minimal toxicity against melanoma cells. Conclusion: In general, the results confirm that SLNs can be an efficient delivery platform for the topical delivery of lycopene as a natural anti-oxidant and anti-melanogenic agent.

Background: Bronchopulmonary dysplasia (BPD) is a common chronic lung disease in the respiratory system of premature infants. Gm15886, as a lncRNA, is highly expressed in lung tissue of BPD newborn mice. Aims: This study aimed to clarify the roles of the Gm15886 gene in the pathogenesis of BPD mice by determining the expression of Gm15886 and Hipk1 in lung tissues. Methods: Sequence and localization of the Gm15886 gene and the related information of its adjacent genes were obtained using the UCSC browsing tool. The targeting gene of the Gm15886 was predicted using the Ensemble database and double luciferase assay. Neonatal C57BL/6J mice were exposed to 95% hyperoxia for 7 days to generate the hyperoxia-induced BPD mouse model. RT-PCR assay was used to detect Gm15886, Hipk1, and VEGF gene transcriptions in lung tissues in the development process of BPD (0, 3, 5, and 7 days). The pathological changes in lung tissues and Hipk1/VEGF gene transcription in lung tissues were detected in the Gm15886 gene silenced BPD mice. Results: Gm15886 gene transcription in lung tissues was significantly increased in mice of the hyperoxia model group compared to that in the air control group (p Conclusions: Gm15886-Hipk1 signaling pathway plays a critical role in the pathogenesis of BPD through modulating Hipk1 and VEGF gene transcription. This study might provide a theoretical basis for the treatment of BPD.

Background: Diabetes mellitus (DM) is a metabolic disorder in which blood sugar levels are elevated over a prolonged period of time. SGLT2 inhibitors have recently demonstrated positive effects on diabetes care by minimizing hyperglycemia through decreased glucosuria. Objective: The aim was to carry out molecular docking and ADMET studies of 1,2,4 triazole and 1,2,4 oxadiazole scaffolds as SGLT2 inhibitors. Methods: Structures of newer molecules of two series of 1,2,4 triazoles and 1,2,4 oxadiazoles were drawn by using Chem Draw Ultra 8.0 software. The AutoDock Vina 1.5.6 software was used for the molecular docking studies. In silico ADMET properties were calculated online using admetSAR and pkCSM predictors. Results: We have designed 1563 different 1,2,4 triazoles and 1,2,4 oxadiazoles as SGLT2 inhibitors. A total of 14 compounds from both the triazole and oxadiazole series were shown to have better binding affinity to the SGLT2 protein than canagliflozin. Among them, SSN 10 and SSON 7 showed the highest docking score and binding affinity of -10.7 kcal/mol and -10.5 kcal/mol, respectively. In silico ADMET properties were also calculated in order to determine physiochemical properties, pharmacokinetics and toxicity of best binding molecules. In addition, these molecules were predicted to be non-carcinogens, showing good oral bioavailability and physiochemical characteristics safer with optimal partition coefficient (LogP = 2.07-5.24). Conclusion: Novel SGLT2 inhibitors were designed based on the scaffold of 1,2,4 triazoles and 1,2,4 oxadiazoles resulting in a new lead molecule with a maximum binding affinity; these molecules were also estimated to be noncarcinogenic with low LogP.

Background: Many contagious diseases have been caused by a variety of nontuberculous mycobacteria, opportunistic pathogens that can cause disseminated or localized diseases, particularly pulmonary, skin, and soft tissue infections. Objective: In this study fifty-five substituted 4-N-alkylated-2-trifluoromethylquinolines were evaluated against five species of nontuberculous mycobacteria: Mycobacterium fortuitum, Mycobacterium chelonae, Mycobacterium abscessus, Mycobacterium kansasii, and Mycobacterium avium. Methods: The antimycobacterial activities of all tested compounds were assessed using the microplate procedure with broth microdilution assay. The most actives were selected for their potential cytotoxic activity against Vero cells. Results: Most of the compounds displayed some activity against M. kansaii, of which 12, 15, 34, 37 and 48 were the most active at 3.12 μg/mL. The derivative 8 was the most active against M. fortuitum at 6.25 μg/mL and the most active against M. chelonae at 3.12 μg/mL. The derivative 2 was the most active against M. avium at 12.5 μg/mL, and 9 the most active against M. abscessus at 12.5 μg/mL. All the most active compounds showed MIC values similar to the references drugs used against these species. Conclusion: 47 compounds displayed some activity against some of the species analyzed, highlighting derivatives 12, 15, 34, 37, and 48, which presented the lower MIC values. Compounds 34 and 37 displayed the highest activity and did not show cytotoxicity against Vero cells. These findings have opened new perspectives for the research of new drugs against these mycobacterial species based on the quinoline nucleus.

Abstract: The world needs a paradigm change from the current views on many plants to secure future food and nutrition. Many neglected and underutilized plants, specially medicinal and aromatic plants, are nutrient dense, appropriate in diversifying diets, provide enough vitamins and micronutrients for people, high resistant to diseases and pests, and can be adapted in many regions and of course with tremendous pharmaceutical benefits. Many of the medicinal plant species which were common in traditional medicine are still neglected and underutilized, especially in developing and under-developing countries. Lack of attention to these plants means their potential medicinal properties are under exploited and underestimated. The searches focused on publications from 1980 to July 2021 using PubMed, Google Scholar, Science Direct, and Scopus databases. Review of the literature was carried out using the following keywords, "medicinal plants", "neglected plants", "underutilized plants", "aromatic plants", "traditional medicine science", and "South America". In this review article, the authors have focused on medicinal values of Schinusterebinthifolius, Uncaria tomentosa, Phyllanthusamarus, Astrocaryum aculeatum, Croton cajucara, Arrabidaea chica, Bauhinia forticata, Copaifera langsdorffii, Cordia verbenacea, Caesalpinia ferrea, Salix alba L., Casearia sylvestris, Carapa guianensis, Costus spicatus, and Eugenia uniflora L., in both modern and traditional science. Although many studies have evaluated the biological characteristics of these plants, little has been done to identify and characterize its chemical components, which is certainly a niche that requires to be further explored.

Background: The heterocyclic nucleus pyrimidine is present in several natural and synthetic chemical analogues and has proved its broad medicinal applications. Further, pyrimidine in the form of parent structure or basic skeleton of RNA and DNA is involved in controlling the immune functioning, and in turn, inflammatory reactions. Objective: The objective of the present study is to evaluate some novel pyrimidine analogues for antiinflammatory action. Method: Molecular docking studies of Indomethacin and selected analogues were carried out with the COX-2 enzyme (PDB: 4ZOL). The synthesis of derivatives of 4-Phenyl-6-(phenylamino)pyrimidine-2-ol derivatives was begun by following Perkin condensation between substituted acetanilides and substituted aromatic aldehydes to yield an intermediate, which in turn produces the required nucleus for treatment with urea. All synthesized compounds were evaluated for in vivo and in vitro anti-inflammatory activity. Result: The docking interaction reflects a good dock score when compared with indomethacin, a potent Anti-inflammatory drug. In the majority of the compounds, pyrimidine was able to form hydrogen bonding while the rest of the part was involved in hydrophobic bonding. All compounds were synthesized in good yield and confirmed by physical and spectral studies. In vitro studies showed that compounds 5a and 5e were better at controlling inflammation than the conventional treatment Antipyrine, while in vivo data showed that compounds 5a, 5c, 5e, and 5h were better at controlling inflammation than the standard drug Antipyrine. Conclusion: The compound with more than one electron releasing group on the aniline moiety of pyrimidine yields a decent result in the synthetic and experimental studies, but the absence of an electron withdrawing group favours stronger anti-inflammatory activity on the target.

Aim: Several new dihydropyridine-based calcium channel blockers have been synthesized and pharmacologically evaluated for the treatment of hypertension Background: Dihydropyridines constitute an important class of calcium channel blockers (CCBs) due to their high potency, wide heterogeneity and tremendous biological usefulness. As a follow-up to our previous studies on 4-aryl-1,4-dihydropyridines as calcium channel blockers for the treatment of hypertension, four new series of methyl ethyl ester substituted 1,4-dihydropyridines are reported. Objectives: The aim of the work was to study the effects of unsymmetrical ester substitutions on calcium channel blocking activity of dihydropyridines (DHPs) while retaining the aminoalkoxy side chain at various positions of the 4-aryl ring. The type and location of the substituents on the 4-aryl ring have been extensively explored to study the structure-activity relationship (SAR) in this series of dihydropyridines as calcium channel blockers. Methodology: The target DHPs were synthesized using modified Hantzsch condensation and further derivatization. The compounds were screened for their inhibitory potential against L-type calcium channels at a single concentration of 10 μM on NG108-15 cells (Neuroblastoma X Glioma). The most potent DHP 12 was also tested for its vasodilatory activity using rat thoracic aortic rings precontracted with KCl (30 mM) and in vivo antihypertensive activity in rats using the tail-cuff method. Results: The newly synthesized DHPs displayed diversified calcium channel blocking activity with compounds 1e, 1h, 2d, 2f, 2h, 6, 9, 11, 12 and 14, producing more than 50% inhibition of veratridine response. 3-imidazolylpropoxy substituted analogue 12 turned out to be the most potent compound of the four series of compounds and produced fairly higher inhibition (78.6%) of veratridine response in comparison to nifedipine (70%) at 10 μM. In addition, compound 12 produced potent vasodilatory and antihypertensive properties. Conclusion: Both location of the side chain and the type of substituent on methyl ethyl ester substituted 4-aryl ring affected the response of dihydropyridine derivatives towards L-type calcium channels.

Abstract: Vitamin K2 products were first applied to Japanese children, which can promote the growth of children's bones and eliminate their growing pain. At the same time, it does little harm to the human body, so it has attracted the attention of some scholars. Later, it was also proved to be effective in treating osteoporosis, especially for postmenopausal women. After years of research, some capabilities of VK2 have been discovered; it has been proved that it has great clinical value in treating osteoporosis, reducing intimal lipid deposition, diabetes, tumor, immune diseases, nervous system diseases and other diseases. There is no doubt that VK2 is an essential nutrient for human health, once vitamin K2 is deficient, it will cause a series of diseases. In recent years, some new evidences show that VK2 can also be used in leukemia and other diseases, which shows that VK2 still has great development potential. As a new adjuvant drug, VK2 has attracted worldwide attention and has been used in the clinic for many years. In this article, we mainly summarized the related research of VK2 in recent years, and expounded on several VK2-related signal pathways and the related mechanisms of these signal pathways in treating various diseases.

Background: Indole and its derivatives play an important role in the synthesis of commercially relevant intermediate molecules required for the synthesis of a wide range of bioactive molecules. Aim: Exploration of the synthesis of novel nonsteroidal anti-inflammatory drugs, as well as their computational studies and pharmacological effects, was aimed as an important component of the present research. Objective: the objective of present work was to synthesize some novel 1-(1H-indol-1-yl)ethanone compounds, analyse their computational effects on the COX-2 enzyme and to test their in vivo analgesic and anti-inflammatory activity. Method: The condensation of 4-(2-(1H-indol-1-yl)-2-oxoethoxy) benzaldehyde with substituted aniline in ethanol in the presence of a catalytic quantity of glacial acetic acid was performed, which yielded the new Indole derivatives. IR, NMR, mass spectroscopy and elemental analysis techniques were used to characterize the structures of new indole derivatives. To estimate the drug-like candidate’s nature, a number of molecular attributes of these derivatives were computed. The synthesized derivatives were docked with a specific reference cyclooxygenase-2 (COX-2) enzyme. The physical similarity of the newly synthesized derivatives (D1-D8) and indomethacin (the reference drug) was determined by evaluating seven physicochemical features by a software. Result: Although the bioavailability/drug likeness was found to be in the standard range, the synthesized compounds exhibited close similarity with those of the reference drug, and subsequent optimization was necessary. Conclusion: The newly synthesized indole derivatives as COX-2 inhibitors were evaluated for their biological properties, which included anti-inflammatory and analgesic efficacy Other: D-7 (1-(1H-indol-1-yl)-2-(4-((4-nitrophenyl)imino)methyl)phenoxy)ethanone) was found to have the strongest anti-inflammatory and analgesic activity amongst the eight target compounds.

Background: Tuberculosis is considered a global health problem; hence, the screening and synthesis of novel tuberculostatic drugs are a necessity. Molecular docking could drastically reduce the time of hit identification; however, initial validation is required to reduce the false-positive results. Objective: Assessment of several searching and scoring algorithms for a custom dataset of hydrazidehydrazone- based tuberculostatics was conducted to obtain a reliable docking protocol for future virtual screening. Methods: Modification in the scoring functions, size of the grid space, and presence of active waters of a GOLD 5.3 docking protocol was conducted. Subsequently, side-chain flexibility and ensemble docking were carried out to assess the role of protein flexibility in the correlation coefficient. In addition, docking simulations with Glide and free binding energy calculations with MM-GBSA were implemented. The Pearson correlation coefficient between the experimental and the acquired in silico data was calculated after each work step. The major interactions between the top-scored ligands and the active site of 2X22 were visualized applying Discovery Studio. Results: An optimized GOLD 5.3 docking protocol led to a drastically enhanced Pearson correlation coefficient of the training set, from 0.461 to 0.823, as well as an excellent pairwise correlation coefficient in the test set - 0,8405. Interestingly, the Glide docking scores and the free binding energy calculations with MM-GBSA did not achieve reliable results. During the visualization of the top-ranked compounds, it was observed that Lys165 played a major role in the formation of stable complexes. Conclusion: It could be concluded that the performance of the optimized GOLD 5.3 docking protocol demonstrated significantly higher reliability against the hydrazide-hydrazone dataset when compared to Glide docking simulations and MM-GBSA free binding energy calculations. The results could be utilized for future virtual screenings.

Purpose: To investigate the underlying mechanism of cardiomyocyte protection of carvedilol based on autophagy and apoptosis. Methods: Neonatal rat ventricular myocytes (NRVMs) were exposed to various concentrations of carvedilol before anoxia, and pretreated with 3-MA or compound C for inhibiting autophagy or p-AMPK expression. CCK-8 colorimeter and flow cytometry were used to determine the cell viability and apoptotic rates. The variation of mRNA and protein was measured by RT-PCR and Western blot. The presence of autophagosomes was observed by electron microscopy. Results: First, we found that carvedilol increased autophagic marker levels in a concentration-dependent manner and the number of autophagosomes in NRVMs. Moreover, carvedilol substantially enhanced the viability and noticeably reduced the CK, MDA and LDH levels and cell apoptosis rate compared with the anoxia group. In addition, carvedilol decreased the levels of caspase-3 and Bim in mRNA and protein, but such effect was blocked by the special autophagy inhibitor-3-MA, and the number of autophagosomes was significantly decreased when treated with 3-MA, indicating that carvedilol exhibited anti-apoptotic and anti-injury effects by inducing autophagy in anoxia NRVMs, but these effects can be abolished by adding 3-MA to suppress autophagy. Finally, the carvedilol treatment-induced autophagy by enhancing the activation of p-AMPK and inhibiting p-mTOR. Electron microscopy presented that the number of autophagosomes was significantly decreased when treating with compound C, indicating that carvedilol induced autophagy in anoxia NRVMs partly by the AMPK-mTOR signaling pathway. Conclusions: Carvedilol has cardioprotection by inducing autophagy against apoptosis partly through the AMPK/mTOR pathway during anoxia in NRVMs.

Background: Pyrimidine and 1,2,4-triazole heterocycles have been linked to a variety of biological and pharmacological properties such as effective bactericides, fungicides, vermicides, insecticides, anticancer and antiviral agents. Accordingly, the synthetic derivatives and analogs of these molecules have attracted attention as potential pharmacological agents. Objective: A novel set of heterocyclic derivatives comprising 1,2,4-triazole, pyrimidine moieties was developed, synthesized, and assessed for their antimicrobial activity. Methods: In this study, we performed ligand-based pharmacophore modeling as a promising design strategy for the design of substituted triazolyl-pyrimidine derivatives as antitubercular agents. The designed compounds were synthesized and characterized by proton, carbon nuclear magnetic resonance spectroscopy, infrared, and mass spectroscopy. Synthesized compounds were screened for anti-TB activity using the agar micro dilution method against M. tuberculosis H37Rv strain. Results: Our results revealed that the target 1,2,4-triazoles 7d, 7e, 7c have potent potency against Gram- (+ve) bacteria S. epidermidis (MICs: 1.7, 3.7, 16.4 μg/mL), whereas final pyrimidines 7c, 7e, 7f, have the strongest antibacterial activity against Gram-(-ve) strain P. aeruginosa (MICs: 3.5, 6.4, 8.4 μg/mL). Among all tested compounds, 7a, 7e, and 7h revealed an outstanding antitubercular activity against M. tuberculosis H37RV strain with MICs of 3.24, 8.93, and 4.70 μg/mL, respectively. The most active ligand 7b reveals highest hydrophobic binding modes with ThrA:127 [2.194 A°], LysA:103 [3.103, 2.164 A°], GlyA:102 [1.713 A°], ArgA:238 [1.713 A°], ValA:101 [2.113 A°] (hydrogen bondings), AspA:129, GluA:201 [Pi-anion], AlaA:246, LeuA:180 [Pi-alkyl] and HisA:179 [3.104 A°] [Pi-Pi], respectively. Conclusion: In this communication, our aim has been verified by the synthesis of 3-methoxy-10,12- dimethyl-8-phenyl-6,7,8,12-tetrahydrobenzo[2,3]oxepino[4,5-d][1,2,4]triazolo[4,3-a] pyrimidine derivatives 7 in which 1,2,4-triazole and pyrimidine moieties with benzoxepine in a single molecular framework were found. After all the above findings, it can be concluded that these molecules become lead molecules for further synthetic and biological evaluation.

Background: In the current Alzheimer’s disease therapy as the preferred treatment are applied acetylcholinesterase inhibitors. Aiming to identify the active pharmacophores necessary for increased acetylcholinesterase inhibitory activity, some docking studies have been applied. Methods: In silico docking evaluation of the binding modes, identification of acetylcholinesterase inhibitory activity in vitro through Ellman’s test and ITC protocol, and the in vivo effect. PAMPA evaluation of the GIT and BBB permeability. Results: In the present study, two series previously synthesized in our laboratory, arylpiperazine derivatives of theobromine were docked into the rhAChE active sites. Ellman’s test outlined molecules LA1 and LA7 as the most active, with IC50 of 0.708 and 0.299 μM, respectively. In the acute toxicity test, LA7 given intraperitoneally in mice showed moderate toxicity with LD50 of 87.5 mg/kg. The new compound, administered i.p. for 12 days at doses 2 mg/kg/day and 4 mg/kg/day, respectively, showed a pronounced acetylcholinesterase inhibitory activity in vivo. Conclusion: The corresponding binding modes were identified, where the docking pose for the studied molecules depends on the protonated state of the nitrogen atom of the piperazine moiety. In the best scored pose for LA7, the xanthine moiety is bound into the catalytic active site (CAS) of acetylcholinesterase, while the arylpiperazine fragment is placed into the peripheral binding site (PAS). For the evaluated selected structures, good permeability through the GIT and BBB assessed by PAMPA was also determined.

Aims: This study documented hepatic tissue's protective activity against oxidative damage mediated experimental models of breast cancer. Background: Gaviola has a long history of improving the protection mechanism against many diseases as an antioxidant and anticancer dietary agent. Objective: The purpose of this study is to establish changes in hepatic profiling, antioxidants, inflammatory cytokine expression, and DMBA-induced hepatic histopathology of mammalian rats. Method: 7,12-dimethylbenz[a] anthracene (DMBA), PAHs, used orally in female Sprague Dawley rats Fifty-seven days-old with breast cancer single-dose diluted in sesame oil of 20 mg/kg/body weight. The cancer-bearing animals had 45 days gastrogavagated at 200 mg/kg/body weight with Graviola. The serum samples were taken at the end of the experiment. The rats were sacrificed to establish the hepatic protective activity of the Graviola by testing hepatic and oxidative stress markers. Result: Graviola therapy shows that enzymatic and non-enzymatic antioxidants and lipid peroxide levels have increased efficiency and have restored the high activity of hepatic marker enzymes such as ALT, AST, ALP, and GGT. To date, hepatic expression of nuclear factor erythroid 2-like 2 (Nfe2l2) and nuclear factor kappa B subunit 1 (Nfkb1) mediated rats have normalized. In addition, histological observations have demonstrated that Graviola's treatment effectively protects the liver from the oxidative damage caused by DMBA, reinforcing its hepatic defensive nature. Conclusion: Graviola therapy improves the efficiency of both enzymatic and non-enzymatic antioxidants and lipid peroxide levels. It also helps in the restoration of other liver enzymes.

Background: Plants have played an essential role in the search for new compounds for the most diverse therapeutic purposes. Recently, more attention has been paid to natural antioxidants because of the possible insecurity of synthetic antioxidants. Objective: The review is aimed at summarizing the most important and common natural antioxidants and their resources from medicinal plants. Method: The research was performed using data bases of PubMed, Google Scholar, Science Direct, Taylor and Francis, etc. to search for all collected scientific publications. Results: The most important medicinal plants with antioxidant activities in Iran are Artemisia, berberry fruit, borage, calendula, coriander, cumin, green tea, hawthorn, jujube, pomegranate, rose, rosemary, black zira, tea, and thyme. Important traditional medicinal plants with antioxidant activities in China are Asparagus, bindii, blueberries, camellia, Chinese bayberry, Chinese bitter melon, Chinese cabbage, Chinese cherry, Chinese jujube, Chinese olive, pomegranate, Chinese rose tea, Chinese toon, Chinese watermelon, black tea, knotweed, Chinese quince, Chinese rhubarb, sumac, wolfberry, dendrobium, drumstick tree, Fiscus species, ginger, ginkgo, goji berry, grape, Jerusalem thorn, kiwifruit seed oil, and liquorice root. Anacardium occidentale L., Ananas comosus (L.) Merril, Baccharis trimera (Less) DC., Carapa guianensis Aubl., Casearia sylvestris Sw., Cordia verbenacea DC., Croton lechleri Müll. Arg., and Eugenia uniflora L. are the main medicinal plants with antioxidant activities in Brazil. Conclusion: Antioxidants are those molecules that are involved in the scavenging of these reactive species causing oxidative stress and are defined as those substances which could prevent the oxidation of the substrate at low concentrations. The main derived exogenous natural antioxidants are derived from medicinal plants, fruits, foods, flowers, and traditional herbal medicines in different parts of the world

Background: Cancer is a complex disease in which some of the cells grow uncontrollably and spread to other parts of the body. Objective: The present study focuses on molecular docking and synthesis of novel flavone derivatives substituted with heterocyclic rings. Objective: The present study focuses on molecular docking and synthesis of novel flavone derivatives substituted with heterocyclic rings. Methods: The anticancer activity of novel flavones against human aromatase enzyme using human breast cancer cell line MCF-7 through MTT assay was demonstrated. The synthesized compounds for the determination of single or double-strand DNA damage through the single-cell electrophoresis/comet assay were evaluated. Results: In this study, we found that the derivative 3M with Morpholine ring showed the highest anticancer potency against the MCF-7 cell line compared to that of other flavone derivatives. Compound 3T showed less cytotoxicity against the MCF-7 cell line. Conclusion: Based on the findings, flavone scaffolds can be selected as a skeleton for the development of heterocyclic amine-containing flavones with the potential to develop as anticancer drugs.

Abstract: Epilepsy is a chronic neurological disorder characterized by periodic and unpredictable seizures affecting the neurobiological, psychological, cognitive, economic, and social well-being of patients. It is one of the causes of concern in developed as well as developing countries as currently marketed drugs are not capable of providing protection against it. Although several heterocyclic moieties have been frequently used as building blocks for the preparation of anticonvulsant drugs, more focused and consistent research on the synthesis of potential molecules with less adverse effects is the need of the hour. It can be concluded on the basis of available research reports that among several heterocyclic compounds, benzo-fused five-membered heterocyclic moieties (benzothiazole and benzimidazole) have been utilized far less than their great potential as building blocks for the synthesis of anticonvulsant drugs. Various reports clearly established that the required pharmacophore model could be easily achieved through benzothiazole and benzimidazole moieties as two hetero atoms and aryl rings are present in the structure. The present study highlights various synthetic approaches for anticonvulsant benzothiazole and benzimidazole derivatives with their structure-activity relationship studies in order to provide a trove of knowledge to medicinal chemists for future research.

Background: Peritoneal adhesions (PA) are a common complication of abdominal operations. Previous studies indicate that inhibition of inflammation and fibrosis at sites of peritoneal damage may prevent the development of intra-abdominal adhesions. Zingiber officinalis Roscoe (ginger) and Panax ginseng (P. ginseng) are herbal products with antioxidant and anti-inflammatory effects that can have restorative properties. Objective: This research aimed to examine the impact of ginger and p. ginseng on prevention of PA in a rat model after surgery. Methods: Following a laparotomy, the wall of the cecum was rubbed to induce intra-abdominal adherence in Wistar rats. Ginger (400mg/kg) and P. ginseng (500mg/kg) were orally adminstered to the animals. The animals were sacrificed on the 10th day after surgery, and the Nair and Leach scoring system was used to assess adhesion. The microscopic histology of the induced cecal adhesions was evaluated. An enzyme-linked immunosorbent assay (ELISA) was used to determined tissue levels of transforming growth factor-beta (TGF-β) on homogenized PA tissue. Real-time PCR was performed to quantify the mRNA expression of IL-1β, TNF-α, Col 1a1, and Col 3a1 in rat tissue. Result: The adhesion score and histopathological rating based on the Nair and Leach scoring criteria showed lower adhesion scores in the group of rats treated with P. ginseng compared to the control group (p Conclusion: The study's outcome recommends that P. ginseng could be an effective agent for preventing the PA and inflammation during the post-operative stage.

Abstract: Enzymes are highly specific catalysts that accelerate reactions in biological systems. Carbonic anhydrase (CA) is an enzyme found in plants, microorganisms, and vertebrates. CA catalyses CO2 hydration/ dehydration. There are different families and isoenzymes of CAs. Fifteen α-CA isoenzymes have been reported in humans. The status of CO2 hydration and dehydration is important for a variety of biological processes. CAs play an important role in many physiological and pathological events in several tissue types. Their levels are increased in some diseases; therefore, CA inhibition has been applied as a therapeutic option. However, the high diversity of these isoenzymes is an important consideration. Isoenzyme- specific CA inhibitors can reduce the side effects of treatment. Some agents containing additional sulfonamides approved for other therapeutic applications, such as topiramate, celecoxib/valdecoxib, sulpiride, and famotidine, have inhibitory effects on CA isoenzymes. These bind to the zinc ion in the CA active site. Recently, research has been conducted on the use of a hybrid form of active ingredient and a CA inhibitor. CA inhibitor-NSAID hybrid compounds demonstrated more efficacy than NSAIDs in arthritis, which has attracted further attention of researchers in conducting research on CA-hybrid drugs.

Abstract: Metastases result from a complicated process in which malignant cells detach from the initial cancerous cells and disseminate to other locations. Few therapy options are available that aim to prevent or counteract metastatic disorders. Identifying novel molecular targets and medications, developing techniques to distribute preexisting chemicals, and combining resources to supervise individualized treatment are all part of this process. Because of its improved sensitivity, accuracy, and multiplexed measurement capacity, nanotechnology has been investigated to recognize extracellular cancer biomarkers, cancer cells, and bioimaging. Nanotechnology is a vast and rapidly expanding field with enormous potential in cancer treatment. Nanoparticles can treat resistant cancers with minimal harm to healthy tissues and organs by targeting cancer stem cells. Nanoparticles can also trigger immune cells, which can help to destroy malignancies. The potential of herbal-based nano formulation as a specialized and high-efficacy therapeutic method opens the path for future research into the screening and use of herbal nanoparticles for cancer treatment. The possible impacts of nanoparticles in the therapy of metastatic cancer, specifically on cell stability, proliferation suppression, eventual interaction with adhesion molecules, and antiangiogenic activity, are discussed in this paper.

Background: A series of aryl-piperazine derivatives of 1,7,8,9-tetrachloro-10,10-dimethoxy-4- azatricyclo [5.2.1.02,6] dec-8-ene-3,5-dione were designed, synthesized, and their biological activities were evaluated. Methods: The chemical structures of the desired compounds were identified by 1H NMR, ESI-MS and elementary analysis. The anti-cancer and anti-angiogenesis activities of the newly synthesized compounds were evaluated by proliferation and migration assays, respectively. Results: The screening results demonstrated that compounds 2 and 5 showed potent anti-tumor activity (IC50 values ranging from 7.1 to 15.9μM) with low cytotoxic activities (IC50＞79.3μM). Although compound 5 had no effects on endothelial proliferation (IC50=65.3μM), it significantly abrogated endothelial cell migration (IC50=6.7μM). Conclusion: This work may impart new direction for the investigations of aryl-piperazine derivatives and lead to the development of potent novel anti-tumor and anti-angiogenesis agents.

Abstract: The computational method is widely used in the field of drug design as well as discovery. It aids the drug discovery and design process by making the procedure faster while also ensuring fewer human errors. Cancer is a condition with the development of abnormal cells expressing features like uncontrolled growth and cell division. This leads to abnormal tissue enlargement and interrupts the normal functioning of the tissue. Computational methods, mainly the molecular docking method, have been utilised extensively in the field of anticancer drug discovery. Docking is a virtual screening method that can be performed on a large database of compounds. Molecular docking helps in identifying the predominant binding modes of a ligand with a protein whose three-dimensional structure is known. The docking process can predict the method of inhibition of the target molecule by the ligand molecule. Utilities of molecular docking include structure-activity relationship studies, lead identification by virtual screening, optimization of the identified lead, combinatorial library design and more. This review discusses the process of docking, its role in anticancer drug discovery, and a comparison of different docking software. Docking programs are used to make the docking process much more quick, efficient, and with fewer human errors, as it mostly depends on computational algorithms. A description of some representative studies in anticancer drug discovery related to selected docking software, Autodock, SwissDock, ICM, GOLD and Glide, are also mentioned. This paper concludes by emphasizing the importance of docking programs in the field of drug discovery and how it influences the modern drug discovery processes.

Aims: The rich ethnomedicinal practices of Dakshina Kannada have received considerable attention, and many treatment methods have been documented. This work aimed to explore the traditional medicinal plants originating from Dakshina Kannada for their anti-SARS-CoV-2 activity by employing in silico methodologies. Methods: Virtual screening of Dakshina Kannada's plants was conducted, which are known for their antiviral activities. Potent plants were shortlisted as Tinospora cordifolia, Nyctanthes arbortristis, Bacopa monnieri, Bombax ceiba, and Curcuma longa based on molecular docking scores. Among these, the active plant Tinospora cordifolia possessed the most potent phytochemicals. Molecular dynamics (MD) simulation and MM/GBSA calculations have been performed on cordifolioside A, syringin, and cordioside. Results: Initially, the selected plants were docked into the active site of SARS-CoV-2 protein. MD simulations were performed to investigate the various conformations and validate the docking results, revealing that cordifolioside A and syringin were more stable than cordioside. The stability of the phytoconstituents in complex with SARS-CoV-2 protein was steady throughout the 100 ns simulation time. Finally, the binding free energies were calculated using the MM/GBSA method. The pharmacophore model has confirmed the hydrogen bond interactions, and PASS prediction determined their antiviral activities. Conclusion: Thus, the present study identified the most potent plant from Dakshina Kannada against the SARS-CoV-2 virus as Tinospora cordifolia with powerful phytochemicals (cordifolioside A, syringin and cordioside). Furthermore, in vitro and in vivo experiments are needed to provide experimental data to develop anti-SARS-CoV-2 drugs.

Background: Hydatidosis is one of the most common zoonotic diseases affecting general health due to the lack of effective treatment strategies. Hydatid cysts are commonly treated with benzimidazole (BZ) derivatives. However, their management is fraught with complications. Objective: This systematic review discusses recent efforts toward developing benzimidazole-based antihydatid nanodrugs. Methods: Data were retrieved using PRISMA guidelines from several databases, such as Scopus, Science Direct, PubMed, Web of Science, Ovid, Google Scholar, and Cochrane. Relevant articles published in English and Persian were retrieved in December 2021. Keywords related to the search process (combined or singular) included echinococcosis, hydatidosis, hydatid cysts, cystic echinococcosis, protoscolicidal effect, albendazole (ALB), mebendazole (MBZ), solid lipid nanoparticles (SLNs), in vitro and in vivo. Results: Twenty-three research articles were eligible for further analysis after considering the inclusion/ exclusion criteria. This study indicates that ALB is the most prevalent synthetic drug incorporated into nanoparticles (n = 68.4%). Additionally, the study examined nanoparticles containing ALB sulfoxide (n = 31.5%). A total of three studies (n = 25%) were conducted with SLNs and two (n = 16.6%) with lipid nanocarriers (NLCs). BALB/c mice (58.3%) were used most frequently in vivo studies. Moreover, 50% of the laboratory animals were treated orally, and 33% were treated intraperitoneally. Conclusion: As the main treatment option for hydatid, ALB has been studied more thoroughly than other drugs when developing nano-based formulations. Nanomaterials like metal nanoparticles, nanopolymers, SLNs, and nanocrystals are being investigated for antiparasitic drug development to enhance therapeutic effectiveness and reduce side effects. The findings of this study lead to the hypothesis that nanoformulation of antiparasitic drugs may open up new opportunities for developing and formulating effective antihypertensive drugs.

Abstract: The review is aimed at summarizing the most important and common natural antioxidants and their resources from traditional Irani and Chinese medicinal sciences. The most important medicinal plants with antioxidant activities in Iran are Artemisia, berberry fruit, borage, calendula, coriander, cumin, green tea, hawthorn, jujube, pomegranate, rose, rosemary, black zira, tea, and thyme. Important traditional medicinal plants with antioxidant activities in China are Asparagus, bindii, blueberries, camellia, Chinese bayberry, Chinese bitter melon, Chinese cabbage, Chinese cherry, Chinese jujube, Chinese olive, pomegranate, Chinese rose tea, Chinese toon, Chinese watermelon, black tea, knotweed, Chinese quince, Chinese rhubarb, sumac, wolfberry, dendrobium, drumstick tree, Fiscus species, ginger, ginkgo, goji berry, grape, Jerusalem thorn, kiwifruit seed oil, and licorice root. The present review article highlights the most important medicinal plants which have been used in Iran and China as traditional herbal medicines for hundreds of years due to their tremendous antioxidant activities.

Background: Chlorogenic acid (CGA), a polyphenolic substance extracted from many traditional Chinese medicines, exerts a mitigative effect in dementia, including Alzheimer’s disease (AD). However, the pathological mechanisms of CGA against AD remain obscure. Objective: To elucidate the core targets, functional characteristics, and underlying mechanisms of CGA against AD using network pharmacology approaches and molecular docking technologies. Methods: GEO database was used to identify the differentially expressed genes (DEGs) in AD. PharmMpper, TargetNet, and SwissTargetPrediction predicted the CGA-related targets. STRING and Cytoscape were employed to construct and analyze the PPI network. Moreover, the Metascape platform was used to perform the GO biological processes and KEGG pathways enrichment. Molecular docking was performed using Autodock Vina software. Results: A total of 5437 targets related to AD were identified with |log2Fold Change (FC)| ≥ 1 and P < 0.05. Based on public databases, 193 putative target genes of CGA were screened. Using the Venn diagram, we found 137 co-targets between CGA and AD. According to the PPI network, 23 core targets for CGA to treat AD were obtained. KEGG enrichment displayed that the PI3K-Akt signaling pathway, MAPK signaling pathway, apoptosis, and NOD-like receptor signaling pathway were several important signaling pathways involved in CGA against AD. SRC, EGFR, HSP90AA1, MAPK1, RHOA, and PIK3R1 were hub targets associated with the activities of CGA against AD. Molecular docking analysis revealed a good binding affinity between CGA and these targets through hydrogen bonds. Conclusion: CGA might exert therapeutic effects in AD by regulating multiple targets and signaling pathways. However, further in vitro and in vivo experiments are required to thoroughly confirm the detailed targets and mechanisms of CGA against AD.

Background: Severe acute respiratory syndrome coronavirus 2 main protease (SARS-CoV-2 Mpro) is an important target for drug development amidst whole variants of coronaviruses, a vital protein for the replication cycle of virus. Objective: The main aim of this study is to discover and recognize the most effective and promising molecules against Mpro enzyme through molecular docking screening of 120 phytochemicals from six different Ayurveda medicinal plants. Methods: The phytochemicals were downloaded from PubChem, and SARS-CoV-2 Mpro was taken from the protein data bank. The molecular interactions, binding energy, and ADMET properties were analyzed. Results: Molecular docking analysis identified 10 phytochemicals, castalagin (-10.4 kcal/mol), wedelolactone (-8.0 kcal/mol), arjungenin (-7.7 kcal/mol), betulin (-7.7 kcal/mol), galbacin (-7.6 kcal/mol), shinpterocarpin (-7.6 kcal/mol), liquirtin (-7.4 kcal/mol), cordioside (-7.3 kcal/mol), licopyranocoumarin (-7.3 kcal/mol), and daucosterol (-7.1 kcal/mol) from different kinds of ayurvedic medicinal plants’ phytochemicals possessing greater affinity against Mpro of SARS-CoV-2. Two molecules, namely castalagin and wedelolactone, with low binding energies were the most promising. Furthermore, we carried out MD simulations for the castalagin complexes based on the docking score. Conclusion: Molecular ADMET profile estimation showed the docked phytochemicals to be safe. The present study suggested that active phytochemicals from medicinal plants could inhibit Mpro of SARSCoV- 2.

Abstract: Based on network pharmacology methods and molecular docking technology, the targets of action of tauroursooxycholic acid (TUDCA) were predicted using the Swiss Target Prediction database. In addition, the potential TUDCA anti-inflammatory targets were obtained via mapping with antiinflammatory targets in the Genecards database. Protein-protein interactions (PPI) and ingredient-targetpathway (ITP) networks were constructed using the STRING database and Cytoscape software. The GO and KEGG enrichment analysis of potential targets were carried out via the David database, and the combination of TUDCA with the key targets were verified via molecular docking. The network showed that 81 targets were involved in the positive regulation of transcription by RNA polymerase II promoter, signal transduction, protein phosphorylation and another 259 biological processes. This highlighted the adjustment of 61 signaling pathways, such as cancer-related pathways, PI3K-Akt, and cAMP. Three key anti-inflammatory targets, MAPK3, SRC and EGFR, were screened using network analysis. The results from the molecular docking analysis showed that the TUDCA molecule had good binding activities with the three key targets. The study also found that TUDCA exhibited multi-target and multi-pathway characteristics, and preliminary explorations indicated anti-inflammatory mechanisms Background: Non-steroidal anti-inflammatory drugs, such as aspirin, have achieved good results in relation to treating inflammation, but these drugs are often accompanied by side effects. Tauroursodeoxycholic acid (TUDCA) has achieved good inflammation treatment results, with its unique ingredients, natural, safe and effective characteristics, and has therefore become a widely used anti-inflammatory drug. Objective: To explore the anti-inflammatory mechanism of TUDCA and lay a foundation for the further development of TUDCA anti-inflammatory drugs Methods: Based on network pharmacology methods and molecular docking technology, the targets of action of tauroursooxycholic acid (TUDCA) were predicted using the Swiss Target Prediction database. In addition, the potential TUDCA anti-inflammatory targets were obtained via mapping with antiinflammatory targets in the Genecards database. Protein-protein interactions (PPI) and ingredient-targetpathway (ITP) networks were constructed using the STRING database and Cytoscape software. The GO and KEGG enrichment analysis of potential targets was carried out via the David database, and the combination of TUDCA with the key targets was verified via molecular docking. Results: The network showed that 81 targets were involved in the positive regulation of transcription by RNA polymerase II promoter, signal transduction, protein phosphorylation and another 259 biological processes. This highlighted the adjustment of 61 signaling pathways, such as cancer-related pathways, PI3K-Akt, and cAMP. Three key anti-inflammatory targets, MAPK3, SRC and EGFR, were screened using network analysis. The results from the molecular docking analysis showed that the TUDCA molecule had good binding activities with the three key targets Conclusion: The study also found that TUDCA exhibited multi-target and multi-pathway characteristics, and preliminary explorations indicated anti-inflammatory mechanisms

Background: Smoking causes cancer, heart attacks, and stroke and leads to asthma and breathing problems. Nicotine replacement therapy (NRT) is considered one of the most widely accepted methods to quit smoking. However, it can lead to relapsed physical and psychological dependence. Aim: The present study aimed to explore propranolol, as a model drug to treat relapsed physical and psychological dependence due to NRT in smoking cessation. Furthermore, for its effective management, the transdermal drug delivery system has opted for the effective and long-term release of propranolol. Objective: The objective of the present study was to investigate and establish the molecular associations between propranolol with different targets associated with smoking cessation. Material and Methods: The molecular association of propranolol with eight different potential targets, namely, Acetylcholine Binding Protein (AChBP), Cannabinoid Receptor, CB1 and CB2, Monoamine oxidase (MAO), human dopamine D3 receptor, kainite, Leu- biogenic amine transporters (BAT) and α- type peroxisome proliferator-activated receptor, was studied via molecular simulation models. Polymeric films containing propranolol HCI were prepared and evaluated to select a suitable formulation for developing transdermal drug delivery systems (TDDS). Films containing different ratios of HPMC K4M, HPMC 15M, and Sodium CMC were prepared by the solvent evaporation technique using PEG 4000 incorporated as a plasticizer, and SLS was used to act as a penetration enhancer. Manufactured transdermal films were physically evaluated for thickness, weight uniformity %, moisture content %, moisture uptake %, drug content % and folding endurance. Results: Results indicated that propranolol can interact with all eight receptors at the active binding site. It was found to show considerable interaction with Acetylcholine Binding Protein (AChBP), MAO, human dopamine D3 receptor, kainite, and Leu- biogenic amine transporters (BAT) with the binding energy of -6.27, -6.74, -7.07, -6.84, and -6.63 kcal/mol, respectively. The release rate of propranolol HCI decreased linearly with increasing polymer concentration in the film and depended on the film thickness. In contrast, the quantity of drug release was proportional to the square root of time. Kinetic data based on the release exponent, ‘n’ in the Peppas model showed that n values were between 0.95 and 1.08, indicating that drug release from polymer matrix was predominantly by diffusion with swelling. Conclusion: Transdermal drug delivery of propranolol could act as a potential regulator of all studied targets associated with physical and psychological dependence associated with NRT and smoking cessation. Furthermore, propranolol-loaded transdermal patches with optimized release could be utilized to deliver the drug with optimum bioavailability for a considerable time.

Background: Thiazoles are an important class of heterocyclic compounds with many biological effects, including anticholinesterase activity. Objective: The purpose of this work was to synthesize new thiazole derivatives and evaluate as acetylcholinesterase inhibitors (AChEIs) for Alzheimer’s disease. Methods: A series of new N-acyl-4-(4-aminoalkoxy-phenyl)-thiazole-2-amine derivatives was designed and synthesized. Ellman assay protocol was used for the AchE and BuChE inhibitory activity. To correlate better the drug-like property, the theoretical prediction was calculated using Mol inspiration software 2015 online. The potential binding mode of compounds with AChE and BuChE was investigated by the molecular docking simulation. Results: All synthesized compounds exhibited a certain inhibitory activity on AChE and 5p had the most effective selective inhibitory effect on AChE. The inhibitory form of 5p on AChE was shown to be a combination of competitive and noncompetitive inhibition, according to enzyme kinetic tests. Docking simulation studies revealed that the binding energy of 5p with AChE was lower than that of it with BuChE, which also explained the selective inhibitory activity of 5p on AChE. Conclusion: These results provided valuable information for the design of potent AChEIs, and it was believed that 5p could be a promising lead structure for its further development for the treatment of AD.

Background: Epoxide hydrolases comprise an important class of enzymes that have critical functions in the detoxification of xenobiotics and regulation of signaling molecules. In addition to epoxides, oxetanes have recently been identified as novel substrates of microsomal epoxide hydrolase (mEH). Oxetanes are common scaffolds used in medicinal chemistry design to improve potency and drug-like properties. Metabolism of oxetanes by mEH can result in high uncertainties in the prediction of human clearance due to extrahepatic contribution and large interindividual variability. Therefore, reducing mEH-mediated oxetane metabolism is highly desirable to minimize its contribution to clearance. Objective: The aim of the study is to evaluate whether quantum mechanical parameters are able to predict the hydrolytic rate of mEH-mediated oxetane metabolism in order to guide medicinal chemistry design in order to minimize mEH contribution to clearance. Methods: Quantum mechanics modeling was used to evaluate the hydrolytic rate of twenty-three oxetanes by mEH. All modeling studies were performed with the Maestro software package. Results: The results show that LUMO energy is highly correlated with the diol formation rate of oxetane hydrolysis by mEH for compounds that are structurally similar, while other quantum mechanical parameters are less predictive. The data suggest that the intrinsic reactivity determines the hydrolytic rate of oxetanes. This occurs when the orientations of the molecules in the mEH active site are similar. Predictions of mEH substrate metabolic rates using LUMO are most accurate when comparing subtle structural changes without drastic changes in MW and chemotype. Conclusion: The study suggests that LUMO energy can be used to rank-order oxetanes for their hydrolytic rate by mEH for structurally similar compounds. This finding enables the medicinal chemistry design to reduce mEH-mediated oxetane metabolism based on the calculated LUMO energy.

Background: Mutations occurring in the epidermal growth factor receptor of the tyrosine kinase family concerned with non-small cell lung cancer have been specifically targeted. Objectives: The library design and R-group enhancement technique have been carried out on the pre existing marketed drugs to increase the binding affinity of the designed novel compounds. The screening of compounds was done using a flexible docking protocol. Methods: Molecular docking studies provided information about binding pockets and interactions of molecules with the mutant (PDB: 4I1Z) as well as wild-type (PDB: 4I23) EGFR enzymes. The flexible docking was well supported by ADMET and molecular dynamic simulation studies. Results: On the basis of docking score and protein-ligand interactions, the highest-scoring molecule was selected for molecular dynamics simulation, providing a complete insight into the ligand interaction and saturation Conclusion: The screened molecules can act as potential EGFR inhibitors in the management of drug resistance.

Backgrounds: Li Kun Zhi Ji (LKZJ) is a traditional Chinese medicine formula that effectively improves the immune system. However, the mechanism of its action against cancer remains unknown. Our study aimed to determine whether LKZJ inhibits the growth of the human colon cancer cell line HCT-116, and we performed in vitro experiments to further explore the associated molecular mechanisms. Objective: We explored the antitumor function and the mechanism of LKZJ against human colon cancer cells. Methods: We selected the effective components of LKZJ. Then, the potential targets of these components were obtained against colon cancer, and an “LKZJ-targets-colon cancer” network was constructed. After that, a CCK-8 assay was used to assess cell viability. Next, apoptosis was analyzed with PI/Annexin V assay using flow cytometry. Finally, western blotting was carried out to determine the expression levels of the protein. Results: We obtained 36 effective LKZJ components and identified 225 candidate targets acting on colon cancer. We demonstrated that the cell viability of HCT-116 cells had significantly decreased after treatment of LKZJ. The suppression of HCT-116 proliferation by LKZJ through inducing apoptosis was determined using Flow cytometry. In addition, mitochondria-associated apoptosis was stimulated, and the down-regulation of Bcl-2 and up-regulation of Bax and Bad were observed. LKZJ also attenuated the PI3K/Akt signaling pathway through western blotting. Conclusion: Our study revealed that LKZJ induced HCT-116 cell line apoptosis through the PI3K/Akt apoptotic pathway. Our results indicated that LKZJ could be a possible therapeutic agent against human colon cancer.

Background: An ongoing global public health concern is the emerging COVID-19 pandemic triggered by acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Mpro, a main protease of SARSCoV- 2, has been established as a potential drug target because of its direct role in viral replication and ability to infiltrate the multiple host pathways. Objective: This research aims to classify new therapeutic drug candidates who may be repositioned for COVID-19 therapeutics. Methods: We have taken similar drug compounds of Dexamethasone and targeted the main protease of SARS-CoV-2 (Mpro) along with the key molecules involved in the 'cytokine storm.' Further, we did MD simulations and calculated the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) on the active site of the main protease of SARS-CoV-2 (Mpro) and TNF-α, IL-6, & IL-1β to explore the binding affinity and stability. Results: Based on our study outcome, Triamcinolone emerged as the most promising inhibitor of the main protease of SARS-CoV-2 (Mpro) and the cytokine storm molecules, i.e., TNF-α, IL-6, and IL-1β. Conclusion: This research investigates the repositioning of COVID-19 drugs as a new therapeutic application.

Background:: Adverse effects induced by upper GIT release of mycophenolic acid (MPA) and its prodrug mycophenolate mofetil (MMF) have created a great deal of concern in the treatment of inflammatory bowel disease (IBD). Objective:: The goal of this work was to create a polymer-based prodrug (MDS) by attaching MPA to dextran to enable colon-targeted drug delivery and, as a result, minimize the adverse effects of MPA and MMF. Methods:: MPA was conjugated with dextran via a bio-cleavable ester bond utilizing the EDCI coupling process. MDS was characterized by spectral analysis. The degree of substitution was estimated by complete hydrolysis of the conjugate in phosphate buffer (pH= 9.0). The prodrug was screened for gastrosparing potential using TNBS-induced colitis model in Wistar rats. Results:: Physicochemical parameters, such as degree of substitution (9.32 mg MPA/100mg of MDS), DSC study (Melting point: 194.3°C), and molecular weight (70307 Da) were determined. The significant mitigating effect of MDS on quantifying parameters of TNBS-induced colitis, i.e., disease activity score rate (0.72±0.35), colon to body weight ratio (0.024±0.003), MPO activity (36.9±0.67mU/100mg of tissue), ulcerogenic potential (2.85±0.08), and histopathological data showed that prodrug restored distorted colonic architecture to normal. Conclusion:: Hydrophilicity was improved, allowing for more effective transport of MPA to the colon. In TNBS-induced colitis, the prodrug was found 1.5 times more efficient than MPA at lowering quantifiable markers of colonic inflammation. Histopathology data showed that MDS might be developed as a potential approach for directing MPA to the colon for the treatment of IBD.

Background: Pandemic of COVID-19 has gathered up the surrounding respiratory diseases such as asthma. The need to combat asthma is an unanswerable question nowadays and about 20-30% of people are getting into the trap of asthma. Objectives: The mechanistic involvement of GPCR receptors in the protuberant signaling pathway such as Neuropeptide S receptor 1 (NPSR1 receptor) acts as a projected entry that needs to be inhibited for the prohibition of asthma. Methods: Exaggerative G-proteins of NPSR1 receptors are exposed as a target through GPCR modeling to point drug targeting. Three Drug-Drug Conjugates (DDCs) are designed through the combination of nine chemical compounds through methylene bridges and selection was done based on docking energy and ADMET profiling. Designation of three Monoclonal Antibody Conjugates (MACs) is expedited using single monoclonal antibodies, linked through EAAAK linkers and the best conjugate was valued based on docking energy, allergenicity, toxicity, and surface accessibility leading towards cloning and expression. Results: The best Drug-Drug Conjugate was Fluoroquinolone and 1-Indanone conjugate which possessed -7.7 Kcal/mol docking energy, lipophilicity 6.41, water solubility 1.19e-09 mg/ml, and pharmacokinetics -8.31 cm/s, indicating it to act as best drug candidate. The best Monoclonal Antibody Conjugate was Ustekinumab and Belimumab conjugate which retained -383.1 Kcal/mol docking energy, computed as non-allergen and nontoxic. Conclusion:: The use of MACs and DDCs may prove an effective treatment for lethal diseases like asthma and the future exertion will support the in vitro synthesis delivered in this study of conjugation against bronchial diseases.

Introduction:: This study aims to use a Quality by Design (QbD) approach to formulate and optimize Trandolapriloro-dispersible tablets. The central composite design tool was utilized to assess the scientific understanding of independent input variables and output responses to construct a design space for regulatory flexibility. Oro-dispersible Tablets (ODT) can also be used to deliver drugs directly to the oral mucosa, bypassing first-pass hepatic metabolism and potentially accelerating the process. Methodology:: The concentrations of super disintegrant and dry compressible binder were selected as independent variables. Disintegration time in seconds and % friability was selected as dependent variables. Polynomial equations were used to predict the quantitative effect of independent variables at various levels on response variables. Results and Discussion: The pre-compression parameters suggested that the flow characteristics were quite excellent. All tablets prepared in the above experiments were evaluated for pharmaco-technical properties and found to be within the required limits using the direct compression method. The angle of repose of the dry blends from each formulation batch (F1 to F9) ranged from 29.03° to 33.67°. All formulation batches had a loose bulk density of 0.31 + 0.07 to 0.37 + 0.91 g/cm3 and a tapped density of 0.41+ 0.02 to 0.46+ 0.16 g/cm3, respectively. The compressibility index was determined to be between 1.65 + 0.17 to 19.93 + 0.47 . Hausner's ratio was between 1.14 + 0.88 to 1.19 + 0.32. The thickness of the tablets ranged from 2.07 + 0.54 to 2.52 + 0.12 mm. The tablets were found to have a hardness of 3.08 + 0.14 to 3.67 + 0.41 kg/cm2. The weight of the tablets prepared ranged from 50 + 0.09 to 52 + 0.56 mg on average. Tablet friability was 0.52 + 0.54 to 0.83 + 0.10 %, and the disintegration time ranged between 27 and 58 seconds. All of these parameters were found under the acceptable limit of pharmacopoeias. The increase of Crospovidone concentration decreased the disintegration time and increased % friability. Whereas increasing the concentration of microcrystalline cellulose increased the disintegration time and decreased the % friability. Contour plots clarified the link between independent and dependent variables. The most cost-effective batch was chosen based on these plots within the desired range because the actual and projected values suggested by the full model were very close to each other; the statistical model is mathematically valid. Conclusion:: The results showed that the proposed design for developing trandolapriloro-dispersible tablets with optimal properties was effective.

Objective: Hepatocellular carcinoma is one of the leading causes of cancer-related death worldwide. Experimental studies reported that some plants in the genus of Psoralea (Fabaceae family) show anticancer potential. The present study aimed to evaluate the effects of Psoralea drupacea extract (PDE) on HepG2 liver cancer cells. Methods: The proliferation, cell cycle, and migration of HepG2 cells were determined by thiazolyl blue tetrazolium bromide test, propidium iodide staining, and scratch assay, respectively. The effects of PDE on the activity of matrix metalloproteinases (MMPs) and angiogenesis were evaluated by the gelatin zymography method and chicken chorioallantoic membrane model, respectively. Results: The culture of HepG2 cells in the presence of PDE (24 hr and 48 hr) significantly reduced their viability (at a concentration of ≥ 50 µg/mL) and increased the percentage of cells in the sub-G1 stage. PDE also increased the antiproliferative and proapoptotic activities of doxorubicin (3 and 6 µg/mL). The extract significantly decreased the generation of reactive oxygen species and lipid peroxidation in the cells. Moreover, PDE (25 and 50 µg/mL) significantly suppressed the migration ability of HepG2 cells, which was associated with inhibition in the activity of MMP2 and MMP9 (50 µg/mL). Furthermore, treatment with PDE significantly reduced the number and diameter of vessels in the chick chorioallantoic membrane. Conclusion: PDE decreased the survival and cell cycle progression of liver cancer cells through a mechanism other than oxidative stress. This extract also showed an anti-angiogenesis effect and diminished the migration ability of HepG2 cells by inhibiting MMP activity

Introduction: Amygdalin (AMG) is a plant-based agent that has many therapeutic applications. Metabolism of this herbal remedy may cause cytotoxicity in cells. Objective: In this study, the role of rhodanese (RH) enzyme against the cyanide of amygdalin has been investigated in human and mouse cell lines in vitro. MethodS: We analyzed the cytotoxicity, morphologic changes, apoptotic effects, and gene expression alterations resulting from treatment with AMG and AMG combined with RH (AMG-RH) in mouse fibroblasts (L929) and human dermal fibroblasts (HDF) cell lines. ResultS: The lowest half-maximal inhibitory concentration (IC50) values were 87.95±3.63 mg/ml and 80.82±2.13 mg/ml at 72 h in both cell lines. Cell viability of both cell lines was significantly decreased after AMG treatment; however, it increased following treatment with AMG-RH for 24, 48, and 72 h. Morphological changes were observed in both cell lines after AMG treatment for 72 h. AMG-RH combination did not cause any significant morphological alterations in either cell line. Conclusion: The apoptosis rates were increased in both cell lines treated with AMG and decreased in AMG-RH treatment for 72 h. BAX, CASP-3, BCL-2, and TST genes were upregulated after treatment with AMG for 72 h in both cell lines. BCL-2 and TST genes were upregulated, while BAX and CASP3 were downregulated after treatment with AMG-RH for 72 h. The findings of this study indicate the IC50 dose of AMG could cause cytotoxicity in HDF and L929 cell lines. Furthermore, it was found that the RH enzyme could decrease AMG cytotoxicity and might have a protective role against AMG.

Introduction: Corneal neovascularization disease is an important clinical symptom of many ocular surface disorders, and the use of anti-vascular endothelial growth factor (anti-VEGF) drugs is considered the most promising treatment method. Method: Ranibizumab (RB) is one of the few anti-VEGF drugs approved by the FDA in the treatment of ophthalmic diseases, but the special synthetic route leads to a short biological half-life, and therapeutic concentration cannot be maintained for a long time in clinical treatment. Therefore, we aim to develop a low immunogenicity sustained release system to improve the bioavailability of RB. RB was loaded on bovine milk-derived exosomes (MEXOs), and the in vitro release profile and pharmacokinetic characteristics were detected. RB was continuously release from the MEXOs (2 days, 60 h). The tubular network formation experiment of human umbilical vein endothelial cells showed that the MEXOs enhanced the inhibitory effects of RB on VEGF-induced tube formation, as confirmed by a cell proliferation experiment. Results: In vivo experiments showed that RB-loaded bovine milk-derived exosomes (RB-MEXOs) increased the precorneal residence time and half-life period of RB in New Zealand white rabbits. Conclusion: These results suggested that RB-MEXOs is conducive to the maintenance of effective RB concentration in vivo, and their use is potential strategy for treating corneal vascularization.