A series of six/five member (E/Z)-Goniothalamin analogs were synthesized from commercially available (3,4-dihydro-2H-pyran-2-yl)methanol/5-(hydroxymethyl)dihydrofuran-2(3H)-one in three steps with good to moderate overall yields and their cytotoxicity against lymphoblastic leukemic T cell line (Jurkat E6.1) have been evaluated. Among the synthesized analogs, (Z)-Goniothalamin appeared to be the most active in cytotoxicity (IC50 = 12 μM). Structure-activity relationship study indicates that introducing substituent in phenyl ring or replacing phenyl ring by pyridine/naphthalene, or decreasing the ring size of lactones (from six to five member) do not increase the cytotoxicity.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
Current research is based on the identification of novel inhibitors of α-amylase enzyme. For that purpose, new hybrid molecules of hydrazinyl thiazole substituted chromones 5-27 were synthesized by multi-step reaction and fully characterized by various spectroscopic techniques such as EI-MS, HREI-MS, 1H-NMR and 13C-NMR. Stereochemistry of the iminic bond was confirmed by NOESY analysis of a representative molecule. All compounds 5-27 along with their intervening intermediates 1-4, were screened for in vitro α-amylase inhibitory, DPPH and ABTS radical scavenging activities. All compounds showed good inhibition potential in the range of IC50 = 2.186-3.405 µM as compared to standard acarbose having IC50 value of 1.9 ± 0.07 µM. It is worth mentioning that compounds were also demonstrated good DPPH (IC50 = 0.09-2.233 µM) and ABTS (IC50 = 0.584-3.738 µM) radical scavenging activities as compared to standard ascorbic acid having IC50 = 0.33 ± 0.18 µM for DPPH and IC50 = 0.53 ± 0.3 µM for ABTS radical scavenging activities. In addition to that cytotoxicity of the compounds were checked on NIH-3T3 mouse fibroblast cell line and found to be non-toxic. In silico studies were performed to rationalize the binding mode of compounds (ligands) with the active site of α-amylase enzyme.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
Oral paclitaxel (PTXL) formulations freed from cremophor® EL (CrEL) is always in utmost demand by the cancerous patients due to toxicities associated with the currently marketed formulation. In our previous investigation [Int. J. Pharm. 2014; 460:131], we have developed an oral oil based nanocarrier for the lipophilic drug, PTXL to target bioavailability issue and patient compliance. Here, we report in vivo antitumor activity and 28-day sub-chronic toxicity of the developed PTXL nanoemulsion. It was observed that the apoptotic potential of oral PTXL nanoemulsion significantly inhibited the growth of solid tumor (59.2 ± 7.17%; p
Matched MeSH terms: Drug Evaluation, Preclinical/methods
In the quest for discovering potent antimicrobial agents with lower toxicity, we envisioned the design and synthesis of nalidixic acid-D-(+)-glucosamine conjugates. The novel compounds were synthesized and evaluated for their in vitro antimicrobial activity against Gram positive bacteria, Gram negative bacteria and fungi. Cytotoxicity using MTT assay over L6 skeletal myoblast cell line, ATCC CRL-1458 was carried out. In vitro antimicrobial assay revealed that 1-ethyl-7-methyl-4-oxo-N-(1,3,4,6-tetra-O-acetyl-2-deoxy-D-glucopyranose-2-yl)-[1,8]-naphthyridine-3-carboxamide (5) and 1-ethyl-7-methyl-4-oxo-N-(2-deoxy-D-glucopyranose-2-yl)-[1,8]-naphthyridine-3-carboxamide(6) possess growth inhibitory activity against resistant Escherichia coli NCTC, 11954 (MIC 0.1589 mM) and Methicillin resistant Staphylococcus aureus ATCC, 33591 (MIC 0.1589 mM). Compound (5) was more active against Listeria monocytogenes ATCC 19115 (MIC 0.1113 mM) in comparison with the reference nalidixic acid (MIC 1.0765 mM). Interestingly, compound (6) had potential antifungal activity against Candida albicans ATCC 10231 (MIC <0.0099 mM). Remarkably, the tested compounds had low cytotoxic effect. This study indicated that glucosamine moiety inclusion into the chemical structure of the marketed nalidixic acid enhances antimicrobial activity and safety.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
Imatinib mesylate is an antineoplastic agent which has high absorption in the upper part of the gastrointestinal tract (GIT). Conventional imatinib mesylate (Gleevec) tablets produce rapid and relatively high peak blood levels and requires frequent administration to keep the plasma drug level at an effective range. This might cause side effects, reduced effectiveness and poor therapeutic management. Therefore, floating sustained-release Imatinib tablets were developed to allow the tablets to be released in the upper part of the GIT and overcome the inadequacy of conventional tablets.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
The aphrodisiac effect of Eurycoma longifolia Jack (0.5 g/kg) was evaluated in noncopulator male rats using an electrical cage. Fractions of E. longifolia Jack decreased the hesitation time of noncopulator male rats, throughout the investigation period. Furthermore, it possessed a transient increase in the percentage of the male rats responding to the right choice, more than 50% of the male rats scored "right choice" after 3 weeks post-treatment and the effect became more prominent after 8 weeks post-treatment (only 40-50% of the control male rats responded to the right choice) using the electrical copulation cage. Hence, this study lends further support to the use of the plant by indigenous populations as a traditional medicine for its aphrodisiac property.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
The aim of this study was to prepare a lipid-based self-microemulsifying drug delivery system (SMEDDS) to increase the solubility and oral bioavailability of a poorly water-soluble compound, buparvaquone (BPQ).
Matched MeSH terms: Drug Evaluation, Preclinical/methods
The limited antibiotic options for effective control of methicillin-resistant Staphylococcus aureus infections has led to calls for new therapeutic approaches to combat this human pathogen. An alternative approach to control MRSA is through the use of anti-infective agents that selectively disrupt virulence-mediated pathways without affecting microbial cell viability or by modulating the host natural immune defenses to combat the pathogen.
Matched MeSH terms: Drug Evaluation, Preclinical/methods*
Screening of aqueous extract of Phyllantus niruri (PL), Zingiber zerumbet (ZG), Eurycoma longifolia (TA-a and TA-b) and Andrographis paniculata (AP) to determine their blood glucose lowering effect were conducted in normoglycaemic and Streptozotocin-induced hyperglycaemic rats. Significant reduction in blood glucose level at 52.90% was shown when hyperglycaemic rats were treated with 50 mg/kg body weight (BW) aqueous extract of AP. This effect is enhanced when freeze-dried material was used, where 6.25 mg/kg BW gave 61.81% reduction in blood glucose level. In the administration of TA-a and TA-b, positive results in hyperglyacaemic rats were only obtained when 150 mg/kg BW of the aqueous extract was used. No significant reduction in blood glucose level were shown in hyperglycaemic rats treated with PL and ZG at all concentrations used (50, 100 and 150 mg/kg BW). In normoglycaemic rats, no significant reduction was noted when all the same extracts were used.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
The interaction of bioactive compounds from ethanolic extracts of selected marine algae samples, separated on chromatographic plates, with nitric/nitrous acid was investigated. The nature of bioactive compounds in the marine algae extracts was characterised using UV absorption spectra before and after reaction with diluted nitric acid, and from the characteristic colour reaction after derivatization with anisaldehyde. It was found that diterpenes from Dictyota dichotoma, an edible brown algae, and sterols from green algae Caulerpa brachypus, bind nitric oxide and may act as a nitric oxide carrier. Although the carotenoid fucoxanthin, found in all brown marine algae also binds nitric oxide, the bonds between nitrogen and the fucoxanthin molecule are much stronger. Further studies are required to evaluate the effects of diterpenes from Dictyota dichotoma and sterols from green algae Caulerpa brachypus to see if they have beneficial cardiovascular effects. The method reported here should prove useful in screening large numbers of algae species for compounds with cardiovascular activity.
Matched MeSH terms: Drug Evaluation, Preclinical/methods*
The drawbacks associated with chemical skin permeation enhancers such as skin irritation and toxicity necessitated the research to focus on potential permeation enhancers with a perceived lower toxicity. Crude palm oil (CPO) is obtained by direct compression of the mesocarp of the fruit of the oil palm belonging to the genus Elaeis. In this research, CPO and tocotrienol-rich fraction (TRF) of palm oil were evaluated for the first time as skin permeation enhancers using full-thickness human skin. The in vitro permeation experiments were conducted using excised human skin mounted in static upright 'Franz-type' diffusion cells. The drugs selected to evaluate the enhancing effects of these palm oil derivatives were 5-fluorouracil, lidocaine and ibuprofen: compounds covering a wide range of Log p values. It was demonstrated that CPO and TRF were capable of enhancing the percutaneous permeation of drugs across full-thickness human skin in vitro. Both TRF and CPO were shown to significantly enhance the permeation of ibuprofen with flux values of 30.6 µg/cm2 h and 23.0 µg/cm2 h respectively, compared to the control with a flux of 16.2 µg/cm2 h. The outcome of this research opens further scope for investigation on the transdermal penetration enhancement activity of pure compounds derived from palm oil.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
Ficus deltoidea leaves extract are known to have good therapeutic properties such as antioxidant, anti-inflammatory and anti-diabetic. We showed that 50% ethanol-water extract of F. deltoidea leaves and its pungent compounds vitexin and isovitexin exhibited significant (p drug for the treatment of diabetes.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
Dysregulation of matrix metalloproteinases (MMPs) activity is known in many pathological conditions with which most of the conditions are related to elevate MMPs activities. Ficus deltoidea (FD) is a plant known for its therapeutic properties. In order to evaluate the therapeutic potential of FD leaf extract, we study the enzymatic inhibition properties of FD leaf extract and its major bioactive compounds (vitexin and isovitexin) on a panel of MMPs (MMP-2, MMP-8 and MMP-9) using experimental and computational approaches. FD leaf extract and its major bioactive compounds showed pronounced inhibition activity towards the MMPs tested. Computational docking analysis revealed that vitexin and isovitexin bind to the active site of the three tested MMPs. We also evaluated the cytotoxicity and cell migration inhibition activity of FD leaf extract in the endothelial EA.hy 926 cell line. Conclusively, this study provided additional information on the potential of FD leaf extract for therapeutical application.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
In the present study, binary oxide (cadmium oxide [CdO])x (zinc oxide [ZnO])1-x nanoparticles (NPs) at different concentrations of precursor in calcination temperature were prepared using thermal treatment technique. Cadmium and zinc nitrates (source of cadmium and zinc) with polyvinylpyrrolidone (capping agent) have been used to prepare (CdO)x (ZnO)1-x NPs samples. The sample was characterized by X-ray diffraction (XRD), scanning electron microscopy, energy-dispersive X-ray (EDX), transmission electron microscopy (TEM), and Fourier transform infrared (FTIR) spectroscopy. XRD patterns analysis revealed that NPs were formed after calcination, which showed a cubic and hexagonal crystalline structure of (CdO)x (ZnO)1-x NPs. The phase analysis using EDX spectroscopy and FTIR spectroscopy confirmed the presence of Cd and Zn as the original compounds of prepared (CdO)x (ZnO)1-x NP samples. The average particle size of the samples increased from 14 to 33 nm as the concentration of precursor increased from x=0.20 to x=0.80, as observed by TEM results. The surface composition and valance state of the prepared product NPs were determined by X-ray photoelectron spectroscopy (XPS) analyses. Diffuse UV-visible reflectance spectra were used to determine the optical band gap through the Kubelka-Munk equation; the energy band gap was found to decrease for CdO from 2.92 to 2.82 eV and for ZnO from 3.22 to 3.11 eV with increasing x value. Additionally, photoluminescence (PL) spectra revealed that the intensity in PL increased with an increase in particle size. In addition, the antibacterial activity of binary oxide NP was carried out in vitro against Escherichia coli ATCC 25922 Gram (-ve), Salmonella choleraesuis ATCC 10708, and Bacillus subtilis UPMC 1175 Gram (+ve). This study indicated that the zone of inhibition of 21 mm has good antibacterial activity toward the Gram-positive B. subtilis UPMC 1175.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
A series of novel aurones bearing amine and carbamate functionalities at various positions (rings A and/or B) of the scaffold was synthesized and evaluated for their acetylcholinesterase and butyrylcholinesterase inhibitory activities. Structure-activity relationship study disclosed several potent submicromolar acetylcholinesterase inhibitors (AChEIs) particularly aurones bearing piperidine and pyrrolidine moieties at ring A or ring B. Bulky groups particularly methoxyls, and carbamate to a lesser extent, at either rings were also prominently featured in these AChEI aurones as exemplified by the trimethoxyaurone 4-3. The active aurones exhibited a lower butyrylcholinesterase inhibition. A 3'-chloroaurone 6-3 originally designed to improve the metabolic stability of the scaffold was the most potent of the series. Molecular docking simulations showed these AChEI aurones to adopt favourable binding modes within the active site gorge of the Torpedo californica AChE (TcAChE) including an unusual chlorine-π interaction by the chlorine of 6-3 to establish additional bondings to hydrophobic residues of TcAChE. Evaluation of the potent aurones for their blood-brain barrier (BBB) permeability and metabolic stability using PAMPA-BBB assay and in vitro rat liver microsomes (RLM) identified 4-3 as an aurone with an optimal combination of high passive BBB permeability and moderate CYP450 metabolic stability. LC-MS identification of a mono-hydroxylated metabolite found in the RLM incubation of 4-3 provided an impetus for further improvement of the compound. Thus, 4-3, discovered within this present series is a promising, drug-like lead for the development of the aurones as potential multipotent agents for Alzheimer's disease.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
The performance of five insecticides (bendiocarb, deltamethrin, DDT, malathion, and imidacloprid) using three application methods (oil-based insecticide films on filter paper, and acetone-based insecticide deposits on two substrates: filter paper and glass) was assessed against a susceptible strain of Cimex lectularius (L.) and two resistant strains of Cimex hemipterus (F.). Substrate type significantly affected (P
Matched MeSH terms: Drug Evaluation, Preclinical/methods*
The dichloromethane bark extract of Garcinia hombroniana yielded one new cycloartane triterpene; (22Z,24E)-3β-hydroxycycloart-14,22,24-trien-26-oic acid (1) together with five known compounds: garcihombronane G (2), garcihombronane J (3), 3β acetoxy-9α-hydroxy-17,14-friedolanostan-14,24-dien-26-oic acid (4), (22Z, 24E)-3β, 9α-dihydroxy-17,14-friedolanostan-14,22,24-trien-26-oic acid (5) and 3β, 23α-dihydroxy-17,14-friedolanostan-8,14,24-trien-26-oic acid (6). Their structures were established by the spectral techniques of NMR and ESI-MS. These compounds together with some previously isolated compounds; garcihombronane B (7), garcihombronane D (8) 2,3',4,5'-tetrahydroxy-6-methoxybenzophenone (9), volkensiflavone (10), 4''-O-methyll-volkensiflavone (11), volkensiflavone-7-O-glucopyranoside (12), volkensiflavone-7-O-rhamnopyranoside (13), Morelloflavone (14), 3''-O-methyl-morelloflavone (15) and morelloflavone-7-O-glucopyranoside (16) were evaluated for cholinesterase enzymes inhibitory activities using acetylcholinesterase and butyrylcholinesterase. In these activities, compounds 1-9 showed good dual inhibition on both the enzymes while compounds 10-16 did not reasonably contribute to both the cholinesterases inhibitory effects.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
Oxadiazole derivatives (6-28) having hydrazone linkage, were synthesized through condensation reaction between benzohydrazide 5 with various benzaldehydes. The oxadiazoles derivatives (6-28) were evaluated for their α-glucosidase inhibitory activity. The IC50 values for inhibition activity vary in the range between 2.64 ± 0.05 and 460.14 ± 3.25 μM. The IC50 values were being compared to the standard acarbose (IC50=856.45 ± 5.60 μM) and it was found that compounds 6-9, 12, 13, 16, 18, 20, 22-28 were found to be more active than acarbose, while other compounds showed no activity. Structure-activity relationship (SAR) studies suggest that oxadiazole benzohydrazones (6-28) inhibitory potential is dependent on substitution of the N-benzylidene part. Compound 18 (IC50=2.64 ± 0.05 μM), which has trihydroxy substitution at C-2', C-4', and C-5' on N-benzylidene moiety, recorded the highest inhibition activity that is three-hundred times more active than the standard drug, acarbose (IC50=856.45 ± 5.60 μM). Compound 23 (IC50=34.64 ± 0.35 μM) was found to be the most active among compounds having single hydroxyl substitution. Shifting hydroxyl from C-2' to C-4' (6) and C-3' (7) reduces inhibitory activity significantly. Compounds with chlorine substituent (compounds 16, 28, and 27) showed potent activities but lower as compared to hydroxyl analogs. Substituent like nitro or methyl groups at any position suppresses enzyme inhibition activity. This reveals the important presence of hydroxyl and halo groups to have enzyme inhibitory potential.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
Four alkaloids comprising two vallesamine, one strychnan, and one pyranopyridine alkaloid, in addition to 32 other known alkaloids were isolated from two Malayan Alstonia species, Alstonia pneumatophora and Alstonia rostrata. The structures of these alkaloids were determined using NMR and MS analyses, and in one instance, confirmed by X-ray diffraction analysis. The nor-6,7-secovallesamine alkaloid, pneumatophorine, is notable for an unusual incorporation of a 3-ethylpyridine moiety in a monoterpenoid indole. The rhazinilam-type alkaloids (rhazinicine, nor-rhazinicine, rhazinal, and rhazinilam) showed strong cytotoxicity toward human KB, HCT-116, MDA-MB-231, and MRC-5 cells, while pneumatophorine, the uleine alkaloid undulifoline, and the strychnan alkaloids, N4-demethylalstogustine and echitamidine, induced concentration dependent relaxation in phenylephrine-precontracted rat aortic rings.
Matched MeSH terms: Drug Evaluation, Preclinical/methods
Phytochemical studies on the stem bark of Garcinia nervosa has resulted in the discovery of one new pyranoxanthone derivative, garner xanthone (1) and five other compounds, 1,5-dihydroxyxanthone (2), 6-deoxyisojacareubin (3), 12b-hydroxy-des-D-garcigerrin A (4) stigmasterol (5), and β-sitosterol (6). The structures of these compounds were elucidated with the aid of spectroscopic techniques, such as NMR and MS. The crude extracts of the plant were assessed for their antimicrobial activity.
Matched MeSH terms: Drug Evaluation, Preclinical/methods