Natural Product-derived Compounds Research Articles

Monoterpene indole alkaloids with anticancer activity from Tabernaemontana species

AbstractIndole alkaloids, predominantly found in plants, are a large group of natural product-derived compounds characterized by a remarkable chemical diversity associated with significant biological properties. Among these, terpenoid indole alkaloids are the largest group of secondary metabolites. Tabernaemontana species (Apocynaceae) are widely distributed in tropical and subtropical regions of the world and used in traditional medicine to treat a variety of illnesses, including tumours. These species biosynthesize large quantities of structurally complex monoterpene indole and bisindole alkaloids. Given the compelling biological properties of indole alkaloids, the phytochemical study of Tabernaemontana species has been widely addressed to identify potential anticancer compounds. Several indole alkaloids have shown antiproliferative effect due to different mechanisms, namely by inducing apoptosis or arresting cell cycle, in diverse cancer cell lines, including multidrug-resistant phenotypes. This review primarily aims to underscore the anticancer activity of indole and bisindole alkaloids isolated from several Tabernaemontana species. Moreover, our recent contributions to the field are also highlighted, focusing on the study of Tabernaemontana elegans. The anticancer evaluation, namely the reversion of P-glycoprotein-mediated multidrug resistance, of two sets of monoterpene indole alkaloid derivatives, obtained by modification of some functional groups of two major monoterpene indole alkaloids, is reviewed, as well as the results obtained for a derivative that targeted homologous recombination DNA repair defects.

Natural products reverse cancer multidrug resistance.

Cancer stands as a prominent global cause of death. One of the key reasons why clinical tumor chemotherapy fails is multidrug resistance (MDR). In recent decades, accumulated studies have shown how Natural Product-Derived Compounds can reverse tumor MDR. Discovering novel potential modulators to reduce tumor MDR by Natural Product-Derived Compounds has become a popular research area across the globe. Numerous studies mainly focus on natural products including flavonoids, alkaloids, terpenoids, polyphenols and coumarins for their MDR modulatory activity. Natural products reverse MDR by regulating signaling pathways or the relevant expressed protein or gene. Here we perform a deep review of the previous achievements, recent advances in the development of natural products as a treatment for MDR. This review aims to provide some insights for the study of multidrug resistance of natural products.

Comparative study of the mechanism of natural compounds with similar structures using docking and transcriptome data for improving in silico herbal medicine experimentations.

Natural products have successfully treated several diseases using a multi-component, multi-target mechanism. However, a precise mechanism of action (MOA) has not been identified. Systems pharmacology methods have been used to overcome these challenges. However, there is a limitation as those similar mechanisms of similar components cannot be identified. In this study, comparisons of physicochemical descriptors, molecular docking analysis and RNA-seq analysis were performed to compare the MOA of similar compounds and to confirm the changes observed when similar compounds were mixed and used. Various analyses have confirmed that compounds with similar structures share similar MOA. We propose an advanced method for in silico experiments in herbal medicine research based on the results. Our study has three novel findings. First, an advanced network pharmacology research method was suggested by partially presenting a solution to the difficulty in identifying multi-component mechanisms. Second, a new natural product analysis method was proposed using large-scale molecular docking analysis. Finally, various biological data and analysis methods were used, such as in silico system pharmacology, docking analysis and drug response RNA-seq. The results of this study are meaningful in that they suggest an analysis strategy that can improve existing systems pharmacology research analysis methods by showing that natural product-derived compounds with the same scaffold have the same mechanism.

Effects of Natural Product-Derived Compounds on Inflammatory Pain via Regulation of Microglial Activation.

Inflammatory pain is a type of pain caused by tissue damage associated with inflammation and is characterized by hypersensitivity to pain and neuroinflammation in the spinal cord. Neuroinflammation is significantly increased by various neurotransmitters and cytokines that are expressed in activated primary afferent neurons, and it plays a pivotal role in the development of inflammatory pain. The activation of microglia and elevated levels of pro-inflammatory cytokines are the hallmark features of neuroinflammation. During the development of neuroinflammation, various intracellular signaling pathways are activated or inhibited in microglia, leading to the regulation of inflammatory proteins and cytokines. Numerous attempts have been conducted to alleviate inflammatory pain by inhibiting microglial activation. Natural products and their compounds have gained attention as potential candidates for suppressing inflammatory pain due to verified safety through centuries of use. Many studies have also shown that natural product-derived compounds have the potential to suppress microglial activation and alleviate inflammatory pain. Herein, we review the literature on inflammatory mediators and intracellular signaling involved in microglial activation in inflammatory pain, as well as natural product-derived compounds that have been found to suppress microglial activation. This review suggests that natural product-derived compounds have the potential to alleviate inflammatory pain through the suppression of microglial activation.

Design, synthesis and evaluation of the novel chalcone derivatives with 2,2-dimethylbenzopyran as HIF-1 inhibitors that possess anti-angiogenic potential

Hypoxia-inducible factor-1 (HIF-1) as a key mediator in tumor metastasis, angiogenesis and poor patient prognosis, has been recognized as an important cancer drug target. Up to now, some HIF-1 inhibitors with diverse skeletal structures were reported as anticancer agents, mostly natural product-derived compounds. In this study, we designed and synthesized a series of chalcone-based compounds with 2,2-dimethylbenzopyran using the combination principles to select benzopyrans and chalcones natural products. A novel series of chalcone-based compounds with 2,2-dimethylbenzopyran were evaluated as HIF-1 inhibitor. HRE luciferase reporter assay demonstrated compounds showed superior HIF-1 inhibitory activity. Among them, compound 16e exhibited the best features: the strongest HIF-1 inhibitory activity (IC50 = 2.38 μM, 3-fold higher than that of LXH-SYP-7). Meanwhile, it also significantly suppressed migration and VEGF-induced invasion of A549 cells in nontoxic concentrations. Additionally, tube formation assay demonstrated its anti-angiogenesis activity. Moreover, the in vivo study indicated that compound 16e could retard angiogenesis in the matrigel plug assay model, and almost no new blood vessels were formed in the suppository when it reached 20 μM. Finally, we also performed a subchronic toxicity test in which doses up to 50 mg/kg were administered orally for 10 days in Kunming mice with no toxic adverse effects and were well tolerated. These findings support the further investigation on the anti-invasive and anti-angiogenic potential of this class of compounds as HIF-1 inhibitor.

Success stories of natural product-derived compounds from plants as multidrug resistance modulators in microorganisms.

Microorganisms evolve resistance to antibiotics as a function of evolution. Antibiotics have accelerated bacterial resistance through mutations and acquired resistance through a combination of factors. In some cases, multiple antibiotic-resistant determinants are encoded in these genes, immediately making the recipient organism a "superbug". Current antimicrobials are no longer effective against infections caused by pathogens that have developed antimicrobial resistance (AMR), and the problem has become a crisis. Microorganisms that acquire resistance to chemotherapy (multidrug resistance) are a major obstacle for successful treatments. Pharmaceutical industries should be highly interested in natural product-derived compounds, as they offer new sources of chemical entities for the development of new drugs. Phytochemical research and recent experimental advances are discussed in this review in relation to the antimicrobial efficacy of selected natural product-derived compounds as well as details of synergistic mechanisms and structures. The present review recognizesand amplifies the importance of compounds with natural origins, which can be used to create safer and more effective antimicrobial drugs by combating microorganisms that are resistant to multiple types of drugs.

High throughput-screening of native herbal compounds identifies taccaoside A as a cytotoxic compound that mediates RAS signaling in cancer stem cells

BackgroundCancer stem cells (CSCs) are characterized by their ability to self-renew, to differentiate into multiple cell types and also drive tumor formation, altogether making them important cellular targets for therapeutic intervention. However, existing CSC-targeting drugs do not significantly improve clinical outcomes. More recently, preclinical studies of natural product-derived compounds have demonstrated their potential usefulness as a therapeutic cancer treatment through their cytotoxic actions on CSCs. PurposeHere, we identify CSC-specific compounds derived from natural products and characterize their putative mechanisms of action in CSCs. MethodsGlioblastoma stem cells (GSCs) were labeled with EGFP via homologous recombination and utilized for a high-throughput screen of 8,344 fractions from 386 herbal medicines. The fractions that extinguished EGFP fluorescence signal were then further characterized by LC-MS/MS. Next, several putative cytotoxic compounds were evaluated for their cytotoxic effects on GSCs, cancer cell lines and immortalized cells using a variety of methods to study cell proliferation (EdU incorporation assay), cell death (cleaved-Caspase-3 immunostaining), DNA damage (comet assay), mitochondrial membrane changes (JC-1 immunostaining), and tumor formation in vitro (soft agar colony forming assay). We also performed surface plasmon resonance analysis, western blotting, and immunohistochemistry to characterize the putative mechanisms underlying the cytotoxic effects of putative compounds on GSCs. Finally, we carried out xenograft tumor growth assays to study the cytotoxic potential of several candidates in vivo. ResultsOur high throughput screen led to the identification of the furostanol saponin taccaoside A and its two homologs from the rhizomatous geophyte Tacca. subflabellata that were cytotoxic to GSCs. Interestingly, the cytotoxic effect of taccaoside A on cell lines was significantly less compared to its homologs, owing to stereochemical differences of a carbon–carbon double bond between C-20 and C-22. Molecular studies revealed that taccaoside A binds to RAS to inhibit downstream effector signaling. Correspondingly, blockade of the interaction between taccaoside A and RAS abolished the inhibitory effect of this compound on CSCs. Furthermore, taccaoside A treatment was effective in limiting tumor cell growth in vivo. ConclusionOur study yielded an effective approach to screen for CSC-specific agents. Through this approach, we identified taccaoside A from the rhizomatous geophyte Tacca. subflabellata are cytotoxic to CSCs through a molecular mechanism that involves RAS binding and suppression of its downstream signaling. Our findings indicate taccaoside A is a potential lead compound for anti-CSC drug discovery.

Synthesis and Inhibitory Activity of Machaeridiol-Based Novel Anti-MRSA and Anti-VRE Compounds and Their Profiling for Cancer-Related Signaling Pathways.

Three unique 5,6-seco-hexahydrodibenzopyrans (seco-HHDBP) machaeridiols A–C, reported previously from Machaerium Pers., have displayed potent activities against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium, and E. faecalis (VRE). In order to enrich the pipeline of natural product-derived antimicrobial compounds, a series of novel machaeridiol-based analogs (1–17) were prepared by coupling stemofuran, pinosylvin, and resveratrol legends with monoterpene units R-(−)-α-phellandrene, (−)-p-mentha-2,8-diene-1-ol, and geraniol, and their inhibitory activities were profiled against MRSA ATCC 1708, VRE ATCC 700221, and cancer signaling pathways. Compounds 5 and 11 showed strong in vitro activities with MIC values of 2.5 μg/mL and 1.25 μg/mL against MRSA, respectively, and 2.50 μg/mL against VRE, while geranyl analog 14 was found to be moderately active (MIC 5 μg/mL). The reduction of the double bonds of the monoterpene unit of compound 5 resulted in 17, which had the same antibacterial potency (MIC 1.25 μg/mL and 2.50 μg/mL) as its parent, 5. Furthermore, a combination study between seco-HHDBP 17 and HHDBP machaeriol C displayed a synergistic effect with a fractional inhibitory concentrations (FIC) value of 0.5 against MRSA, showing a four-fold decrease in the MIC values of both 17 and machaeriol C, while no such effect was observed between vancomycin and 17. Compounds 11 and 17 were further tested in vivo against nosocomial MRSA at a single intranasal dose of 30 mg/kg in a murine model, and both compounds were not efficacious under these conditions. Finally, compounds 1–17 were profiled against a panel of luciferase genes that assessed the activity of complex cancer-related signaling pathways (i.e., transcription factors) using T98G glioblastoma multiforme cells. Among the compounds tested, the geranyl-substituted analog 14 exhibited strong inhibition against several signaling pathways, notably Smad, Myc, and Notch, with IC50 values of 2.17 μM, 1.86 μM, and 2.15 μM, respectively. In contrast, the anti-MRSA actives 5 and 17 were found to be inactive (IC50 > 20 μM) across the panel of these cancer-signaling pathways.

Epithelial to Mesenchymal Transition in Lung Cancer: Potential EMT-Targeting Natural Product-derived Compounds.

Epithelial to mesenchymal transition (EMT) is the cellular transition process of epithelium-associated phenotypes and behaviors into mesenchymal phenotypes. EMT is linked with cancer, and it is believed to be an important factor facilitating the motility and invasive activity of solid tumor cells. EMT facilitates the capability of cancer cells to metastasize because it promotes cell survival in detached conditions and facilitates the establishment of new tumors. In lung cancer, EMT has garnered considerable attention because of its importance in metastasis and has been recognized as an important target for anticancer drug therapy. Several studies have pointed out the promising activities of natural product-derived compounds and other agents that have EMT-suppressive activities and may facilitate the development of novel strategies for lung cancer management. In this review, we discuss the recent discoveries regarding the fundamental signaling regulating EMT and identify molecular targets for anti-EMT activities of the natural product-derived compounds. We also highlight the anti-EMT effect of natural compounds with their molecular targets and mechanisms of action that may benefit the understanding of and support the development of EMT targeting therapy.

Free Linoleic Acid and Oleic Acid Reduce Fat Digestion and Absorption In Vivo as Potent Pancreatic Lipase Inhibitors Derived from Sesame Meal

Pancreatic lipase catalyzes the cleavage of triacylglycerols at the oil–water interface, and is known as the dominant determiner of dietary fat digestion. Reducing dietary fat digestion and absorption by modulating the activity of pancreatic lipase has become a favorable strategy to tackle obesity. Orlistat is, at present, the only pancreatic lipase inhibitor approved for the treatment of obesity; however, an array of gastrointestinal adverse effects associated with orlistat limits its tolerability. As a safe alternative to orlistat, a number of natural product-derived compounds with varying degrees of pancreatic lipase inhibitory activity have been reported. We herein reported that bioactivity-guided fractionation of sesame meal led to the identification of free linoleic acid and oleic acid as potent inhibitors of porcine pancreatic lipase in vitro with an IC50 of 23.1 µg/mL (82.4 µM) and 11.7 µg/mL (41.4 µM), respectively. In rats, a single oral dose of the mixture of these fatty acids significantly suppressed the elevation of blood triacylglycerol level following fat intake. These results substantiate the role of free linoleic acid and oleic acid as a novel class of natural product-derived functional molecules that act as pancreatic lipase inhibitors, and their potential for healthy, routine-based weight management.

High-Throughput Screening Campaign Identified a Potential Small Molecule RXFP3/4 Agonist.

Relaxin/insulin-like family peptide receptor 3 (RXFP3) belongs to class A G protein-coupled receptor family. RXFP3 and its endogenous ligand relaxin-3 are mainly expressed in the brain with important roles in the regulation of appetite, energy metabolism, endocrine homeostasis and emotional processing. It is therefore implicated as a potential target for treatment of various central nervous system diseases. Since selective agonists of RXFP3 are restricted to relaxin-3 and its analogs, we conducted a high-throughput screening campaign against 32,021 synthetic and natural product-derived compounds using a cyclic adenosine monophosphate (cAMP) measurement-based method. Only one compound, WNN0109-C011, was identified following primary screening, secondary screening and dose-response studies. Although displayed agonistic effect in cells overexpressing the human RXFP3, it also showed cross-reactivity with the human RXFP4. This hit compound may provide not only a chemical probe to investigate the function of RXFP3/4, but also a novel scaffold for the development of RXFP3/4 agonists.

A Molecular Modeling Approach to Identify Potential Antileishmanial Compounds Against the Cell Division Cycle (cdc)-2-Related Kinase 12 (CRK12) Receptor of Leishmania donovani.

The huge burden of leishmaniasis caused by the trypanosomatid protozoan parasite Leishmania is well known. This illness was included in the list of neglected tropical diseases targeted for elimination by the World Health Organization. However, the increasing evidence of resistance to existing antimonial drugs has made the eradication of the disease difficult to achieve, thus warranting the search for new drug targets. We report here studies that used computational methods to identify inhibitors of receptors from natural products. The cell division cycle-2-related kinase 12 (CRK12) receptor is a plausible drug target against Leishmania donovani. This study modelled the 3D molecular structure of the L. donovani CRK12 (LdCRK12) and screened for small molecules with potential inhibitory activity from African flora. An integrated library of 7722 African natural product-derived compounds and known inhibitors were screened against the LdCRK12 using AutoDock Vina after performing energy minimization with GROMACS 2018. Four natural products, namely sesamin (NANPDB1649), methyl ellagic acid (NANPDB1406), stylopine (NANPDB2581), and sennecicannabine (NANPDB6446) were found to be potential LdCRK12 inhibitory molecules. The molecular docking studies revealed two compounds NANPDB1406 and NANPDB2581 with binding affinities of −9.5 and −9.2 kcal/mol, respectively, against LdCRK12 which were higher than those of the known inhibitors and drugs, including GSK3186899, amphotericin B, miltefosine, and paromomycin. All the four compounds were predicted to have inhibitory constant (Ki) values ranging from 0.108 to 0.587 μM. NANPDB2581, NANPDB1649 and NANPDB1406 were also predicted as antileishmanial with Pa and Pi values of 0.415 and 0.043, 0.391 and 0.052, and 0.351 and 0.071, respectively. Molecular dynamics simulations coupled with molecular mechanics Poisson–Boltzmann surface area (MM/PBSA) computations reinforced their good binding mechanisms. Most compounds were observed to bind in the ATP binding pocket of the kinase domain. Lys488 was predicted as a key residue critical for ligand binding in the ATP binding pocket of the LdCRK12. The molecules were pharmacologically profiled as druglike with inconsequential toxicity. The identified molecules have scaffolds that could form the backbone for fragment-based drug design of novel leishmanicides but warrant further studies to evaluate their therapeutic potential.

Discovery of Macrolide Antibiotics Effective against Multi-Drug Resistant Gram-Negative Pathogens.

Macrolides are among the most widely prescribed antibiotics, particularly for bacterial lung infections, due to their favorable safety, oral bioavailability, and spectrum of activity against Gram-positive pathogens such as Streptococcus pneumoniae, the most common cause of bacterial pneumonia. Their utility against Gram-negative bacteria is extremely limited and does not include the Enterobacteriaceae or other ESKAPE pathogens. With the increasing development of resistance to current therapies and the lack of safe, oral options to treat Gram-negative infections, extended-spectrum macrolides have the potential to provide valuable treatment options. While the bacterial ribosome, the target of macrolides, is highly conserved across Gram-positive and Gram-negative bacteria, traditional macrolides do not possess the proper physicochemical properties to cross the polar Gram-negative outer membrane and are highly susceptible to efflux. As with most natural product-derived compounds, macrolides are generally prepared through semisynthesis, which is limited in scope and lacks the ability to make the drastic physicochemical property changes necessary to overcome these hurdles.By using a fully synthetic platform technology to greatly expand structural diversity, novel macrolides were prepared with a focus on lowering the MW and increasing the polarity to achieve a physicochemical property profile more similar to that of traditional Gram-negative drug classes. In addition to the removal of lipophilic groups, a critical structural feature for obtaining Gram-negative activity in the macrolide class proved to be the introduction of small secondary or tertiary amines to yield polycationic species potentially capable of self-promoted uptake. Within the azithromycin-like 15-membered azalides, potent activity was seen when small alkyl amines were introduced at the 6'-position of desosamine. The biggest gains, however, were made by replacing the entire C10-C13 fragment of the macrolactone ring with commercially available or readily synthesized 1,2-aminoalcohols, leading to 13-membered azalides. The introduction of a tethered basic amine at the C10-position and systematic optimization of substitution and tether length and flexibility ultimately provided new macrolides that for the first time exhibit clinically relevant antibacterial activity against multi-drug resistant Gram-negative bacteria. A retrospective computational analysis of >1800 fully synthetic macrolides prepared during this effort identified key drivers and optimum ranges for improving permeability and avoiding efflux. In contrast to standard Gram-negative drugs which generally have MWs below 600 and clogD7.4 values below 0, we found that the ideal ranges for Gram-negative macrolides were MW between 600 and 720 and cLogD7.4 between -1 and 3. A total charge of between 2.5 and 3 was also required to provide optimal permeability and efflux avoidance. Thus, Gram-negative macrolides occupy a unique physicochemical property space that lies between traditional Gram-negative drug classes and Gram-positive macrolides.

The crystal structure of AbsH3: A putative flavin adenine dinucleotide-dependent reductase in the abyssomicin biosynthesis pathway.

Natural products and natural product-derived compounds have been widely used for pharmaceuticals for many years, and the search for new natural products that may have interesting activity is ongoing. Abyssomicins are natural product molecules that have antibiotic activity via inhibition of the folate synthesis pathway in microbiota. These compounds also appear to undergo a required [4 + 2] cycloaddition in their biosynthetic pathway. Here we report the structure of an flavin adenine dinucleotide-dependent reductase, AbsH3, from the biosynthetic gene cluster of novel abyssomicins found in Streptomyces sp. LC-6-2.

Overcoming Multidrug Resistance: Flavonoid and Terpenoid Nitrogen-Containing Derivatives as ABC Transporter Modulators.

Multidrug resistance (MDR) in cancer is one of the main limitations for chemotherapy success. Numerous mechanisms are behind the MDR phenomenon wherein the overexpression of the ATP-binding cassette (ABC) transporter proteins P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and multidrug resistance protein 1 (MRP1) is highlighted as a prime factor. Natural product-derived compounds are being addressed as promising ABC transporter modulators to tackle MDR. Flavonoids and terpenoids have been extensively explored in this field as mono or dual modulators of these efflux pumps. Nitrogen-bearing moieties on these scaffolds were proved to influence the modulation of ABC transporters efflux function. This review highlights the potential of semisynthetic nitrogen-containing flavonoid and terpenoid derivatives as candidates for the design of effective MDR reversers. A brief introduction concerning the major role of efflux pumps in multidrug resistance, the potential of natural product-derived compounds in MDR reversal, namely natural flavonoid and terpenoids, and the effect of the introduction of nitrogen-containing groups are provided. The main modifications that have been performed during last few years to generate flavonoid and terpenoid derivatives, bearing nitrogen moieties, such as aliphatic, aromatic and heterocycle amine, amide, and related functional groups, as well as their P-gp, MRP1 and BCRP inhibitory activities are reviewed and discussed.

Natural Compounds from the Marine Brown Alga Caulocystis cephalornithos with Potent In Vitro-Activity against the Parasitic Nematode Haemonchus contortus.

Eight secondary metabolites (1 to 8) were isolated from a marine sponge, a marine alga and three terrestrial plants collected in Australia and subsequently chemically characterised. Here, these natural product-derived compounds were screened for in vitro-anthelmintic activity against the larvae and adult stages of Haemonchus contortus (barber’s pole worm)—a highly pathogenic parasitic nematode of ruminants. Using an optimised, whole-organism screening system, compounds were tested on exsheathed third-stage larvae (xL3s) and fourth-stage larvae (L4s). Anthelmintic activity was initially evaluated on these stages based on the inhibition of motility, development and/or changes in morphology (phenotype). We identified two compounds, 6-undecylsalicylic acid (3) and 6-tridecylsalicylic acid (4) isolated from the marine brown alga, Caulocystis cephalornithos, with inhibitory effects on xL3 and L4 motility and larval development, and the induction of a “skinny-straight” phenotype. Subsequent testing showed that these two compounds had an acute nematocidal effect (within 1–12 h) on adult males and females of H. contortus. Ultrastructural analysis of adult worms treated with compound 4 revealed significant damage to subcuticular musculature and associated tissues and cellular organelles including mitochondria. In conclusion, the present study has discovered two algal compounds possessing acute anthelmintic effects and with potential for hit-to-lead progression. Future work should focus on undertaking a structure-activity relationship study and on elucidating the mode(s) of action of optimised compounds.

Molecular docking and dynamics simulations studies of OmpATb identifies four potential novel natural product-derived anti-Mycobacterium tuberculosis compounds

The outer membrane protein A (OmpATb) of Mycobacterium tuberculosis is a virulence factor that neutralizes the host pH to impede the uptake of hydrophilic antitubercular drugs. Identifying natural compounds with the potential to inhibit OmpATb could allow circumvention of the porin-like activities of OmpATb. Four potential leads comprising ZINC000003958185, ZINC000000157405, ZINC000000001392 and ZINC000034268676 were obtained by virtual screening of 6394 diverse natural products. Characterization of the binding interactions of the potential leads with OmpATb revealed nine critical residues comprising ARG86, LEU110, LEU113, LEU114, ALA115, PHE142, SER145, VAL146, and PHE151. Molecular dynamics simulations also revealed very stable protein-lead complexes. Most residues contributed lower binding energies to the overall molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) binding free energies of the interactions between the molecules and OmpATb protein. Induced Fit Docking (IFD) of the compounds regenerated poses of the molecular docking using AutoDock Vina. These molecules could be starting templates for designing inhibitors to bypass the pore mediating activities of OmpATb. Based on structural similarity, ZINC000034268676 was suggested as a potential scaffold for designing efflux pump inhibitors of the gate mediating activities of OmpATb and may enhance the uptake of hydrophilic drugs to reduce the duration time of tuberculosis treatment. Furthermore, structurally similar compounds available in the DrugBank database with a similarity threshold of 0.7 have been reported to exhibit antitubercular and anti-mycobacterial activities. These biomolecules can be further characterized experimentally to corroborate their antitubercular activity. Also, the skeletons of the molecules can be adopted as sub-structures for the design of future anti-mycobacterial drugs.

Publisher Correction: Integrating yeast chemical genomics and mammalian cell pathway analysis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Hypoglycemic and antioxidant activities of Clerodendrum inerme leaf extract on streptozotocin-induced diabetic models in mice

ObjectiveRecently, much attention has been paid to natural product-derived compounds for antidiabetic drug discovery. More recent studies are being focused on clarifying the bioactivity of plants and derived products. The aim of the present study was to investigate the anti-oxidant and antidiabetic activities of Clerodendrum inerme leaf extract (CILE) in streptozotocin-induced diabetic mice. MethodsC. inerme leaves were analyzed for preliminary phytochemical properties and the content of total phenolic and flavonoid were determined. In vitro anti-oxidant activity was measured using DPPH assay. Streptozotocin-induced diabetic model in mice was applied for in vivo study by the effect of CILE at two dose levels (343 and 686 mg/kg b.w.). ResultsThe results showed that C. inerme leaves contained the major constituents of flavonoids, alkaloids, tannins, triterpenes, and saponins. CILE exhibited the total polyphenol and flavonoid content with 120.458 mg gallic acid equivalent/g dry weight and 4.494 mg hispidulin equivalent/g dry weight, respectively. The anti-oxidant activity of CILE was expressed with IC50 = 25.28 µg/mL. CILE at the doses of 343 mg/kg and 686 mg/kg after 7 d administration exerted a decrease in plasma glucose, protected the liver, kidneys against oxidation stress via increasing glutathione content in the liver, and reduced malondialdehyde content in the liver and kidneys. Pancreatic histological analysis in diabetic mice treated with CILE also showed the pancreatic β-cells regeneration via increasing the size and number of pancreatic islets. ConclusionThese findings suggested that C. inerme leaves had potent antidiabetic and anti-oxidant activities. The results provide reliable scientific base, which is the premise for further research and development of CILE as supplements.

Natural products with SGLT2 inhibitory activity: Possibilities of application for the treatment of diabetes.

Diabetes mellitus currently affects as many as 400 million people worldwide, creating a heavy economic burden and stretching health care resources. A dysfunction of glucose homeostasis underlies the disease. Despite advances in the treatment of diabetes, many patients still suffer from complications and side effects; hence, development of more effective treatments for diabetes is still desirable. SGLT2 is the principle cotransporter involved in glucose reabsorption in the kidney. SGLT2 inhibition reduces glucose reabsorption by the kidney and ameliorates plasma glucose concentration. The interest in natural products that can be used for the inhibition of SGLT2 is growing. The flavonoid phlorizin, which can be isolated from the bark of apple trees, has been used as lead structure due to its inhibitory activity of SGLT1 and SGLT2. Some phlorizin-derived synthetic compounds, including canagliflozin, dapagliflozin, empagliflozin, ipragliflozin, and ertugliflozin, are approved by the food and drug administration to treat type 2 diabetes mellitus (T2DM), whereas others are under clinical trials investigation. In addition, other natural product-derived compounds have been investigated for their ability to improve blood glucose control. The present review summarizes the natural products with SGLT2 inhibitory activity, and the synthetic compounds obtained from them, and discusses their application for the treatment of diabetes.