Lead Molecules For Drug Development Research Articles

Design, synthesis, and computational analysis (molecular docking, DFT, MEP, RDG, ELF) of diazepine and oxazepine sulfonamides: biological evaluation for in vitro and in vivo anti-inflammatory, antimicrobial, and cytotoxicity predictions.

We report the synthesis and extensive characterization of Diazepane and Oxazepane derivatives, followed by their biological evaluation. These compounds were assessed for in vitro and in vivo antimicrobial, anti-inflammatory, and anticancer activities. Among the synthesized molecules, compound 5b demonstrated remarkable antibacterial activity against Staphylococcus aureus and Staphylococcus epidermidis with MIC values of 20 and 40 μg/mL, respectively. Additionally, 5b exhibited potent anti-inflammatory effects both in vitro and in vivo. Advanced computational studies, including DFT, MEP, RDG, and ELF analyses, were performed to understand the electronic distribution and molecular interactions. The bioactivity and physicochemical properties of these derivatives were further predicted using PASS and pkCSM platforms, emphasizing their potential as promising lead molecules in drug development.

Synthesis of tetrazole hybridized with thiazole, thiophene or thiadiazole derivatives, molecular modelling and antimicrobial activity

BackgroundTetrazole-based derivatives and their electronic structures have displayed interesting antimicrobial activity. MethodsThe tetrazole-based hybrids linked with thiazole, thiophene and thiadiazole ring systems have been synthesized through various chemical reactions. The computational method DFT/B3LYP has been utilized to calculate their electronic properties. The antimicrobial effectiveness was investigated against representative bacterial and fungal strains. Additionally, the synthesized derivatives binding interaction was stimulated by docking program against PDB ID: 4URO as a model of the ATP binding domain of S. aureus DNA Gyrase subunit B. ResultsThe structures of the synthesized tetrazole-based derivatives were confirmed by IR, NMR, and Mass spectroscopic data. The DFT/B3LYP method showed that the thiadiazole derivatives 9a–c had lower ΔEH-L than the thiophenes 7a–c and thiazoles 5a–c. The hybrids 5b, 5c, and 7b exhibited proper antibacterial activity against Gram’s +ve bacterial strains (S. aureus and S. pneumonia), while 9a displayed potent activity towards Gram’s -ve bacterial strains (S. typhimurium and E. coli). Meanwhile, derivatives 5a-b, 7a, 7c, and 9c showed good effectiveness towards fungal strain (C. albicans). ConclusionThe study provides valuable tetrazole core-linked heterocyclic rings and opens the door to further research on their electrical characteristics and applications. Tetrazoles and thiazoles have antibacterial properties in pharmacological frameworks, making these hybrids potential lead molecules for drug development. The conclusion summarizes the data and suggests that the synthesized chemicals' interaction with a particular protein domain suggests focused biological activity.

IN VITRO AND IN SILICO ANTIBACTERIAL ACTIVITIES OF SYZGIUM AROMATICUM ESSENTIAL OIL AGAINST BACTERIA ASSOCIATED WITH OTITIS MEDIA IN CHILDREN.

This study investigated the efficacy of the essential oil (EO) of Syzgium aromaticum L. (clove) on the bacteria associated with otitis media. Ear swab samples were collected and bacteria isolated were identified using morphological and biochemical procedures. Essential oil was extracted from the dried flower buds using the hydro-distillation method while physicochemical and phytochemical analysis was done on the oil. Antibiotic susceptibility test and agar well diffusion was used to determine the susceptibility of the isolates to the EO. In - silico analysis was conducted to determine the drugable compound in the EO. Phytochemical analysis of the oil indicated the presence of flavonoids, sterols, phenols, carbohydrates and alkaloids. Physicochemical test of the EO exhibited the presence of eugenol (80.98%) as the most abundant phytocompound. Percentage occurrence of the bacterial isolates are as follows; Proteus mirabilis (31.25%), Staphylococcus aureus (25%), Pseudomonas aeruginosa (18.25%), Proteus vulgaris (3.12%), Moraxella catarrhalis (12.5%), Klebsiella pneumoniae (3.12%) and Staphylococcus epidermidis (6.25%). Zones of inhibition were within the range of 11.5±0.71mm-23.0±2.83mm. In silico studies demonstrated that 16 out of 38 compounds identified passed the ADMET analysis. Various compounds had different binding energies, such as linalool, carvacrol for S. aureus (2NOJ), gamma-eudesmol, eudesmol for Proteus mirabilis (6H2L), eucalyptol, gamma-eudesmol and eudesmol for Proteus vulgaris (4MCX) and Staphylococcus epidermidis (4HBL). This study shows the potency of clove EO as an antibacterial agent and its component as potential lead molecules in drug development and design to combat multi - drug resistance.

Identification of Novel Type Three Secretion System (T3SS) Inhibitors by Computational Methods and Anti-Salmonella Evaluations.

Three type III secretion system (T3SS) inhibitors (compounds 5, 19, and 32) were identified by virtual screening and biological evaluation. These three compounds were evaluated against a panel of Salmonella species strains including S. enteritidis, S. typhi, S. typhimurium, S. paratyphi, and S. abortus equi, and their minimum inhibitory concentrations ranged from 1 to 53 μg/ml. Especially, these compounds showed comparable activity as the of the positive control gatifloxacin towards S. abortus equi. The present results suggest that these new T3SS inhibitors could be used as a potential lead molecule for drug development of anti-Salmonella.

Fine-Tuning of Alkaline Residues on the Hydrophilic Face Provides a Non-toxic Cationic α-Helical Antimicrobial Peptide Against Antibiotic-Resistant ESKAPE Pathogens.

Antibiotic-resistant ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) has become a serious threat to public health worldwide. Cationic α-helical antimicrobial peptides (CαAMPs) have attracted much attention as promising solutions in post-antibiotic era. However, strong hemolytic activity and in vivo inefficacy have hindered their pharmaceutical development. Here, we attempt to address these obstacles by investigating BmKn2 and BmKn2-7, two scorpion-derived CαAMPs with the same hydrophobic face and a distinct hydrophilic face. Through structural comparison, mutant design and functional analyses, we found that while keeping the hydrophobic face unchanged, increasing the number of alkaline residues (i.e., Lys + Arg residues) on the hydrophilic face of BmKn2 reduces the hemolytic activity and broadens the antimicrobial spectrum. Strikingly, when keeping the total number of alkaline residues constant, increasing the number of Lys residues on the hydrophilic face of BmKn2-7 significantly reduces the hemolytic activity but does not influence the antimicrobial activity. BmKn2-7K, a mutant of BmKn2-7 in which all of the Arg residues on the hydrophilic face were replaced with Lys, showed the lowest hemolytic activity and potent antimicrobial activity against antibiotic-resistant ESKAPE pathogens. Moreover, in vivo experiments indicate that BmKn2-7K displays potent antimicrobial efficacy against both the penicillin-resistant S. aureus and the carbapenem- and multidrug-resistant A. baumannii, and is non-toxic at the antimicrobial dosages. Taken together, our work highlights the significant functional disparity of Lys vs Arg in the scorpion-derived antimicrobial peptide BmKn2-7, and provides a promising lead molecule for drug development against ESKAPE pathogens.

A recepto-informatics study of the phytocompounds of <em>Tabernaemontana divaricata</em> (L.) having potential anticancer efficacy for breast cancer

Background: Breast cancer could be a serious global health concern causing the best mortality rate in females. Available synthetic medicine to treat breast cancer are marred by extreme toxicity problems and recommend some alternate route to handle the dreadful disease. The present study is an Insilco effort to identify the antitumor potential of Tabernaemontana divaricata plant metabolites.Materials and Methods: The structure of the Human estrogen Receptor (HER), a possible target of breast cancer was selected as target molecules, retrieved from the protein data Bank (PDB) and therefore the structures of alkaloids compounds are collected from PubChem database. Molecular docking and drug similarity studies were performed for these alkaloids compounds to assess and analyze the anti-breast cancer action.Results: The detailed interaction studies of a few alkaloids (Coronaridine, Voacangine, Voacristine, Catharanthine, and Ibogamine) suggest that the compound could serve as probable lead molecules in drug development. All these five compounds also exhibited the highest binding affinity with human ER more significant than 8.7 Kcal/mol which is more affinity as compared to that of standard drugs Tamoxifen.Conclusion: The results of this study is enforced to design novel anti-cancerous medicine within the coming future. The interaction studies of the standard drug with breast cancer markers serve as a tool to synthesize new compounds of desired effectiveness against the deadly disease.

Posttranslational modifications of α-conotoxins: sulfotyrosine and C-terminal amidation stabilise structures and increase acetylcholine receptor binding.

Conotoxins are peptides found in the venoms of marine cone snails. They are typically highly structured and stable and have potent activities at nicotinic acetylcholine receptors, which make them valuable research tools and promising lead molecules for drug development. Many conotoxins are also highly modified with posttranslational modifications such as proline hydroxylation, glutamic acid gamma-carboxylation, tyrosine sulfation and C-terminal amidation, amongst others. The role of these posttranslational modifications is poorly understood, and it is unclear whether the modifications interact directly with the binding site, alter conotoxin structure, or both. Here we synthesised a set of twelve conotoxin variants bearing posttranslational modifications in the form of native sulfotyrosine and C-terminal amidation and show that these two modifications in combination increase their activity at nicotinic acetylcholine receptors and binding to soluble acetylcholine binding proteins, respectively. We then rationalise how these functional differences between variants might arise from stabilization of the three-dimensional structures and interactions with the binding sites, using high-resolution nuclear magnetic resonance data. This study demonstrates that posttranslational modifications can modulate interactions between a ligand and receptor by a combination of structural and binding alterations. A deeper mechanistic understanding of the role of posttranslational modifications in structure-activity relationships is essential for understanding receptor biology and could help to guide structure-based drug design.

Simultaneous determination of naphtodianthrones, emodin, skyrin and new bisanthrones in Hypericum perforatum L. in vitro shoot cultures

Hypericum perforatum L. (St John's wort) extracts are top-selling herbal medicines for the treatment of various ailments including mild to moderate depression across the world. One of the major bioactive compounds of these extracts is hypericin that is also considered as a lead molecule for drug development. Here, we report on the development of a robust method for the simultaneous quantification of hypericins (hypericin, pseudohypericin, protohypericin and protopseudohypericin), their presumed precursors (emodin and skyrin) and new skyrin derivatives (oxyskyrin, iridoskyrin, rubroskyrin and luteoskyrin). Compounds extracted from the in vitro shoot cultures of H. perforatum L. in ethanol, acetone, 80 % methanol, ethylacetate and dichloromethane were separated by ultra-performance liquid chromatography (UPLC), quantified by photo diode array/ fluorescence (PDA-FLR) and annotated by Q- Exactive Orbitrap mass spectrometer (UPLC-QE-MS). Analyses of the UPLC data revealed that ethanol is the best extractant for the efficient quantification of all target compounds, although all of them could also be extracted in acetone and 80 % methanol. The extractants as well as the method of detection proved to be important for the efficient quantification of naphtodianthrones. Our results are expected to significantly contribute to the dissection of the hypericin biosynthesis pathway and the quality control of Hypericum extracts in the pharmaceutical industry.

Ximenynic acid: A versatile lead molecule for drug development

Ximenynic acid: A versatile lead molecule for drug development

Novel MASP-2 inhibitors developed via directed evolution of human TFPI1 are potent lectin pathway inhibitors

The lectin pathway (LP) of the complement system is an important antimicrobial defense mechanism, but it also contributes significantly to ischemia reperfusion injury (IRI) associated with myocardial infarct, stroke, and several other clinical conditions. Mannan-binding lectin–associated serine proteinase 2 (MASP-2) is essential for LP activation, and therefore, it is a potential drug target. We have previously developed the first two generations of MASP-2 inhibitors by in vitro evolution of two unrelated canonical serine proteinase inhibitors. These inhibitors were selective LP inhibitors, but their nonhuman origin rendered them suboptimal lead molecules for drug development. Here, we present our third-generation MASP-2 inhibitors that were developed based on a human inhibitor scaffold. We subjected the second Kunitz domain of human tissue factor pathway inhibitor 1 (TFPI1 D2) to directed evolution using phage display to yield inhibitors against human and rat MASP-2. These novel TFPI1-based MASP-2 inhibitor (TFMI-2) variants are potent and selective LP inhibitors in both human and rat serum. Directed evolution of the first Kunitz domain of TFPI1 had already yielded the potent kallikrein inhibitor, Kalbitor® (ecallantide), which is an FDA-approved drug to treat acute attacks of hereditary angioedema. Like hereditary angioedema, acute IRI is also related to the uncontrolled activation of a specific plasma serine proteinase. Therefore, TFMI-2 variants are promising lead molecules for drug development against IRI.

Strategy for Tumor-Selective Disruption of Androgen Receptor Function in the Spectrum of Prostate Cancer.

Testosterone suppression in prostate cancer is limited by serious side effects and resistance via restoration of androgen receptor (AR) functionality. ELK1 is required for AR-dependent growth in various hormone-dependent and castration-resistant prostate cancer models. The amino-terminal domain of AR docks at two sites on ELK1 to coactivate essential growth genes. This study explores the ability of small molecules to disrupt the ELK1-AR interaction in the spectrum of prostate cancer, inhibiting AR activity in a manner that would predict functional tumor selectivity. Small-molecule drug discovery and extensive biological characterization of a lead compound. We have discovered a lead molecule (KCI807) that selectively disrupts ELK1-dependent promoter activation by wild-type and variant ARs without interfering with ELK1 activation by ERK. KCI807 has an obligatory flavone scaffold and functional hydroxyl groups on C5 and C3'. KCI807 binds to AR, blocking ELK1 binding, and selectively blocks recruitment of AR to chromatin by ELK1. KCI807 primarily affects a subset of AR target growth genes selectively suppressing AR-dependent growth of prostate cancer cell lines with a better inhibitory profile than enzalutamide. KCI807 also inhibits in vivo growth of castration/enzalutamide-resistant cell line-derived and patient-derived tumor xenografts. In the rodent model, KCI807 has a plasma half-life of 6 hours, and maintenance of its antitumor effect is limited by self-induced metabolism at its 3'-hydroxyl. The results offer a mechanism-based therapeutic paradigm for disrupting the AR growth-promoting axis in the spectrum of prostate tumors while reducing global suppression of testosterone actions. KCI807 offers a good lead molecule for drug development.

Discovery of a Novel Nav1.7 Inhibitor From Cyriopagopus albostriatus Venom With Potent Analgesic Efficacy

Spider venoms contain a vast array of bioactive peptides targeting ion channels. A large number of peptides have high potency and selectivity toward sodium channels. Nav1.7 contributes to action potential generation and propagation and participates in pain signaling pathway. In this study, we describe the identification of μ-TRTX-Ca2a (Ca2a), a novel 35-residue peptide from the venom of Vietnam spider Cyriopagopus albostriatus (C. albostriatus) that potently inhibits Nav1.7 (IC50 = 98.1 ± 3.3 nM) with high selectivity against skeletal muscle isoform Nav1.4 (IC50 > 10 μM) and cardiac muscle isoform Nav1.5 (IC50 > 10 μM). Ca2a did not significantly alter the voltage-dependent activation or fast inactivation of Nav1.7, but it hyperpolarized the slow inactivation. Site-directed mutagenesis analysis indicated that Ca2a bound with Nav1.7 at the extracellular S3–S4 linker of domain II. Meanwhile, Ca2a dose-dependently attenuated pain behaviors in rodent models of formalin-induced paw licking, hot plate test, and acetic acid-induced writhing. This study indicates that Ca2a is a potential lead molecule for drug development of novel analgesics.

Metabolomics of Medicinal Plants - A Versatile Tool for Standardization of Herbal Products and Quality Evaluation of Ayurvedic Formulations

Secondary metabolites from plants provide lead molecules for drug development. Metabolomics is a modern omic-technique for comprehensive analysis of phytochemicals. Advances in mass spectrometry (MS) based platforms like GC-MS and LC-MS, helped in separation and identification of several metabolites. Such analysis can be a valuable tool for identifying potential biomolecules from medicinal plants. Despite the potential use, metabolomics data of Indian medicinal plants and spices are extremely limited. Similarly, metabolomic studies on Ayurvedic formulations, e.g. Triphala/Trikatu, are lacking. Our review emphasizes the importance of metabolomics of Indian medicinal plants, crucial for quality evaluation and scientific validation of herbal products.

Visible-Light-Induced Arylthiofluoroalkylations of Unactivated Heteroaromatics and Alkenes

Visible-light-induced arylthiofluoroalkylations of unactivated heteroaromatics and alkenes have been developed utilizing readily available arylthiofluoroalkyl sources. This method enables simultaneous installation of sulfur and fluoroalkyl moieties, two important functional groups, which demonstrates its potential use for late-stage modifications in the synthesis of functional molecules. This method can be easily utilized to fine-tune the properties of lead molecules in drug development by controlling the number of fluorine atoms in the reagents.

Abstract A17: Identification and characterization of small molecules targeting MYC-cofactor interactions

Abstract Our aim is to develop specific inhibitors targeting the interaction between the oncoprotein/transcription factor MYC and its cofactors. MYC-family genes (MYC, MYCN, MYCL) are involved in over half of all cancers, including many childhood cancers such as neuroblastoma, medulloblastoma, leukemia and lymphoma, and is often strongly associated with poor prognosis. This emphasizes the need to identify clinically relevant MYC inhibitors. It regulates numerous genes involved in cell growth, metabolism, apoptosis, senescence and other processes. MYC is functionally dependent on interaction with the dimerization partner MAX and with several cofactors involved in different aspects of transcription regulation. Targeting such interactions with low Mw compounds is a plausible way to inhibit the transcriptional function of MYC. We have established several techniques to visualize MYC-cofactor interactions in living (BiFC, split Gaussia Luc) or fixed (isPLA) cells to screen small Mw compound libraries for MYC/cofactor-interaction inhibitors. In MYC/MAX BiFC and Gaussia Luc screens, 15 compounds were identified that directly or indirectly inhibit MYC/MAX interactions in cells. Several of these compounds including analogues are potent inhibitors of MYC/MYCN-dependent proliferation and transformation in neuroblastoma, leukemia/lymphoma and other cancer cells by inducing apoptosis or senescence. One of these, #2, and analogues completely inhibit MYC/MAX interactions in vitro by binding MYC. Another compound, 2XU, inhibit MYC/MAX interactions in sub-nanomolar concentration. We are evaluating the biological activities of these molecules further in different MYC-driven cell culture systems, and are elucidating their mechanisms of action by X-ray crystallography, FRET and SPR. In vivo studies with some of these molecules in mouse tumor models is ongoing. Furthermore, extended screens for finding molecules targeting MYC and other cofactor interactions, such as E3-ligases, are ongoing. The MYC inhibitors identified here have the potential to become important tools in the studies of MYC function in cells and in vivo as well as lead molecules for drug development for treatment of MYC-driven tumors. Citation Format: Alina Castell, Qinzi Yan, Karin Ridderstråle, Lars-Gunnar Larsson. Identification and characterization of small molecules targeting MYC-cofactor interactions. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A17.

Phytochemical composition and antioxidant activity ofFicus elasticaRoxb. (Moraceae) leaves

The aim of this study is to analyze the phytochemical composition and antioxidant activity of Ficus elastica (F. elastica). Antioxidant activity of methanolic extract of Ficus elastica leaves was evaluated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay, total antioxidant activity test, iron chelating activity test and reducing power assay. Antimicrobial activity and Cytotoxicity of F. elastica was determined by agar well diffusion method and brine shrimp lethality test respectively, while total phenolic and flavonoid contents of the extract were measured by Folin-Ciocalteau reagent method and aluminum chloride method respectively. The extract showed significant (p<0.05) dose dependent antioxidant activity in various in vitro antioxidant methods. F. elastica also showed broad spectrum antimicrobial activity against Bacillus cereus, Klebsiella pneumoniae, Escherichia coli and Pseudomonas aerugenosa. Brine shrimp lethality activity of F. elastica unveiled significant dose dependent and time dependent cytotoxic activity against brine shrimp nauplii. Phytochemical screening of F. elastica showed the presence of carbohydrates, phenolic, flavonoids, proteins and tannins, which might be responsible for the above reported medicinal properties of the extract. These findings establish F. elastica as a potential source of natural antioxidants, antimicrobial and cytotoxic compounds and in future studies can be established to obtain the lead molecules for drug development.

In Silico Screening of Antibacterial Compounds from Herbal Sources Against Vibrio cholerae.

Background:The prolonged use of antibiotic viz., tetracycline, quinolones, ampicillin, etc., to reduce the infection of cholera, may failed due to the emergence of new Vibrio cholerae antibiotics resistant strains. Moreover, these antibiotics even restricted for patient suffering from severe dehydration. Hence, there is a call to find an alternative therapeutics against V. cholerae. The natures serve different herbs in its lap which might contain several natural therapeutic compounds almost all diseases. Computer-aided designing is the initial steps for screening the novel inhibitors.Objective:To identify and evaluate natural compounds with low side effects with high efficacy against V. cholerae has been done.Materials and Methods:In silico screening, absorption, digestion, metabolism, and excretion (ADME), and docking of herbal compounds have been performed on to the target ToxT (transcriptional activator of V. cholerae). The compound with good ADME properties and drug-likeness property were subjected to docking.Results:From 70 herbal compounds, some compounds such as aloin, campesterol, lupeol, and ursolic acid showed a violation of the rule of five and compounds such as lupeol and beta carotene showed negative binding energy. Luteolin, catechin, brevifolin, etc., compounds were selected based on ADME, drug-likeness property, and docking studies.Conclusion:Two compounds named catechin and luteolin showed better inhibition properties against ToxT and good ADME and drug-likeness property were selected as a better lead molecule for drug development in future. The Genetic Optimization for Ligand Docking fitness score for catechin is 48.74 kcal/mol and luteolin 38.12 kcal/mol.SUMMARY Vibrio cholerae became antibiotic resistance and associated with several cholera epidemic and pandemic. Hence, there is a need to find an alternative therapeutics against V. cholerae. Many herbal compounds present in nature having high medicinal value. From in-silico study, found two compound Luteolin from Tulsi and Catechin from Green Tea which showed good binding energy and druggish property. Abbreviations used: V. cholerae: Vibrio cholera, ADME: Absorption, digestion, metabolism and excretion, CT: Cholera toxin, TCP: Toxin co-regulated Pilus, GOLD: Genetic Optimization for Ligand Docking, Asp: Aspartic acid, Arg: Arginine, Lys: Lysine, Thr: Threonine, Tyr: Tyrosine, KEGG: Kyoto encyclopedia of Genes and Genomes.

Ethnopharmacological analysis of medicinal plants and animals used in the treatment and management of pain in Mauritius

Ethnopharmacological relevancePain is a multi-faceted and multi-factorial condition which is challenging to manage and treat. Conventional therapies such as analgesics, Non-steroidal anti-inflammatory drugs (NSAIDs), and corticosteroids amongst others have been successful to some extent in its management and treatment. Nonetheless, such therapies tend to be accompanied by undesirable effects and have a limited therapeutic range. Consequently, there is a pressing need to probe for novel analgesic and anti-nociceptive drugs from traditional medicines (TM). This study was designed to record, document and analyze herbal and animal-based therapies used for the management and treatment of pain in the tropical of Mauritius. Materials and methodsData was collected via face-to-face interviews with TM users (n=332) and practitioners (n=20). Seven quantitative ethnopharmacological indexes, namely family use value (FUV), use value (UV), informant agreement ratio (IAR), relative frequency of citation (RFC), fidelity level (FL), relative importance (RI) and ethnobotanicity index (EI) were calculated. ResultsA total of 79 plant species distributed within 40 families and 20 polyherbal preparations was recorded. Interestingly, 6 indigenous/endemic plants have been reported for the first time to be in common use for pain management and treatment in Mauritius. The most significant biologically important plant family was Xanthorrhoeaceae with highest FUV. The species which ranked highest according to its UV was Morinda citrifolia L. Morinda citrifolia L. and Ricinus communis L. also scored the highest RFC. The IAR values for the disease categories were high (0.95–0.97). Based on EI, plants species which are known to be useful in TM accounted for 11.5% of the total flora in Mauritius. Coix lacryma-jobi L. (FL=100%) had highest FL for lower back ache. Morinda citrifolia L. scored highest on most of the quantitative indices calculated including RI, which is endorsed by extensive documentation on its versatility and particularly its anti-nociceptive properties. Seven animal species were recorded to be in common use. ConclusionThe present ethnopharmacological study revealed a panoply of TM to be in common use for pain management and treatment in Mauritius. This study has documented for the first time medicinal plants and animal species with potential analgesic and/or anti-nociceptive properties. This study has therefore provided important baseline primary data for the discovery of new lead molecules for drug development geared towards pain management and treatment.

Acetyl and butyryl cholinesterase inhibitory sesquiterpene lactones from Amberboa ramosa.

BackgroundAlzheimer’s disease (AD) is characterized by a progressive memory loss that leads to a profound emotional disturbance in later stages. As no safe and effective drug is yet available for the treatment of AD, secondary metabolites from plants may be instrumental in meeting this challenge. Keeping in view this point we evaluated sesquiterpenes of medicinal plant Amberboa ramosa for their cholinesterase inhibitory activity.ResultsFour sesquiterpene lactones have been isolated from the ethyl acetate soluble fraction of Amberboa ramosa. In which one compound Amberbin C (1) was found to be new while other three Amberin (2), Amberbin A (3), and Amberbin B (4) were previously reported ones. The structures of the isolated compounds were elucidated using different spectroscopic techniques. Isolated compounds were tested for their inhibitory potential against acetyl cholinesterase and butyryl cholinesterase enzymes. All compounds showed excellent inhibitory activities against acetyl cholinesterase and butyryl cholinesterase.ConclusionsA new sesquiterpene lactone has been isolated and fully characterized, the sesquiterpene lactones from Amberboa ramosa showed good inhibitory activities against acetyl cholinesterase and butyryl cholinesterase enzymes, this study indicated that sesquiterpene lactone can become interesting lead molecules in drug development against Alzheimer’s disease (AD).

Abstract 2828: Characterization of protein substrates of PSA: effect of PSA stimulating peptides

Abstract Increased proteolytic activity is associated with cancer, where proteases play a major role in tumor spread and formation of metastases. However, proteases may also inhibit tumor growth. The prostate produces several proteases, the most abundant one being prostate-specific antigen (PSA or kallikrein-related peptidase-3, KLK3). The role of PSA in the prostate, and in particular in prostate cancer, is not well known. However, several functions have been proposed, most of which are based on the protein substrates, which PSA cleaves in vitro. These include both tumor growth promoting and inhibiting activities, e.g., antiangiogenic activity of PSA. We have previously used phage display technology to develop peptides, the synthetic analogs of which stimulate the activity of PSA. These peptides are useful for studying the significance of PSA-activity and potentially for prostate cancer treatment. We analyzed the cleavage of different protein substrates of PSA and found that physiological substrates, semenogelin-1 and −2, are cleaved much more efficiently than other substrates, such as IGFBP-3, fibronectin and galectin-3. The peptides increased the proteolytic activity of PSA towards these protein substrates, but the extent of stimulation and the relative efficiency of peptides were different than with small peptide substrates. We conclude that the peptides can be used to stimulate the activity of PSA towards natural protein substrates. Thus, they may be potential lead molecules for drug development. As most of the studied protein substrates are cleaved with very low efficiency, their relevance as PSA substrates is questionable, especially as prostate produces several other highly active proteases, including several kallikreins and trypsin. As compared to other substrates, semenogelins are very efficiently cleaved by PSA, highlighting the substrate specificity of PSA. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2828. doi:1538-7445.AM2012-2828