DESIGN, SYNTHESIS AND PRELIMINARY PHARMACOLOGICAL EVALUATION OF NEW METFORMIN DERIVATIVES

Objective: The purpose of this work was to enhance oral bioavailability of metformin by incorporation of different amino acid residues through the glycolic acid spacer.Methods: Two series of metformin derivatives (V a-e) and (VI a-e) were synthesized by incorporation of five amino acids (glycine, alanine, phenylalanine, proline and GABA amino butyric acid) and their methyl esters respectively into metformin through glycolic acid spacer and preliminary evaluation for the antihyperglycemic activity was carried out using streptozotocin-induced diabetic rats model.Results: In vivo anti-hyperglycemic activity of the final compounds (V a-e) and (VI a-e) showed that compounds (V b, V c, VI c and V e) produced higher percent of decrease in blood glucose level compared to metformin after 5 h of the treatment while compounds (VI b, VI c, V d, VI d, V e and VI e) showed profound effect after 24 h of the treatment. Although compounds (V a, VI a, V b and V c) showed a significant decrease in blood glucose level at 5 h but their effect diminished at 24 h. Compound (V e) showed higher anti-hyperglycemic effect than metformin and its effect continued up to 24 h.Conclusion: From this study, it was concluded that incorporation of these amino acids or their methyl esters maintained or enhanced the antihyperglycemic effect of metformin.Â

Design, Synthesis and Acute Anti-Inflammatory Evaluation of New Non-Steroidal Anti-Inflammatory Agents Having 4-Thiazolidinone Pharmacophore

Naproxen suffers from general side effects of NSAIDs, owing to the presence of free carboxylic group. The study was aimed to retard the adverse effects of gastrointestinal origin. New series of 4-thiozolidinones derivatives of naproxen were synthesized Va-f. The structures of synthesized compounds have been established on the basis of their spectral FT-IR and 1H NMR data. In vivo acute anti-inflammatory effects of the synthesized compounds were evaluated in rats using egg-white induced edema model of inflammation. The tested compounds and the reference drug produced significant reduction of paw edema with respect to the effect of propylene glycol 50%v/v (control group). Compounds Va-e exhibited potent anti-inflammatory effect than naproxen (50mg/kg, i.p.) at 180-240 min., while compound Vf exhibited lower anti-inflammatory effect. Keywords: Naproxen, 4-Thiazolidinone, Anti-inflammatory activity

DETERMINATION, ISOLATION, AND IDENTIFICATION OF AUCUBIN AND VERBASCOSIDE IN THE LEAVES OF IRAQI PLANTAGO LANCOLETA L. USING DIFFERENT DETECTING METHODS

Objective: Plantago lanceoleta L. (ribwort plantain) is one of the important medicinal herbs which is widespread fortune available in Iraq, that have a wide range of medicinal properties. The aim of this work was to determine, isolate and identify verbascoside and aucubin in Iraqi P. lanceoleta L. by using different chromatographic and spectrometric methods. Methods: Verbascoside and aucubin were isolated and quantified by preparative TLC, and then they were determined by the high-performance thin-layer chromatography (HPTLC) fingerprinting. Aucubin and catalpol in the plant extract were analyzed by liquid chromatography-mass spectrometry (LC-MS); aucubin and verbascoside that isolated from the plant sample were examined by fourier-transform infrared spectroscopy (FT-IR) and LC-MS, respectively. Results: The result showed that the Iraqi P. lanceoleta L. contains 1.74 percent (verbascoside) and 0.24 percent (aucubin) of dry powdered leaves. Each TLC-isolated compound showed a single spot on the HPTLC plate, which give an idea about the purity of the isolated compound. Aucubin (with catalpol) and verbascoside both are detected by LC-MS in different ionization mode. Many functional groups were identified in the TLC-isolated aucubin by FT-IR. Conclusion: The Iraqi P. lanceoleta L. showed a high content of verbasoside, and it is a very rich source for this compound, which can be easily isolated by TLC and subjected to many pharmacological studies. The extract of the young leaves of this plant gave a little amount of aucubin, and it is easy to obtain a higher content from the older leaves

Synthesis and Preliminary Pharmacological Evaluation of New Analogues of Diclofenac as Potential Anti-inflammatory Agents

A group of amine derivatives [4-aminobenzenesulfonamide derivatives, 2-aminopyridine and 2-aminothiazole] incorporated to α-carbon of diclofenac a well known non-steroidal anti-inflammatory drug (NSAID) to increase bulkiness were designed and synthesized for evaluation as  a potential anti-inflammatory agents with expected COX-2 selectivity. In vivo acute anti-inflammatory activity of the selected final compounds (9, 12 and 13) was evaluated in rats using egg-white induced edema model of inflammation in a dose equivalent to (3 mg/Kg) of diclofenac sodium. All tested compounds  produced a significant reduction  in paw edema with respect to the effect of propylene glycol 50% v/v (control group). Moreover, the 4-aminobenzenesulfonamide derivative (compound 9) exhibited superior anti-inflammatory activity compared to diclofenac sodium at times 180-300 minutes with the same onset of action. The results of this study indicate that the incorporation of the selected aromatic amino groups in to diclofenac maintain its anti-inflammatory activity.                                                                                                                              Key words: amine derivatives, anti-inflammatory, diclofenac derivatives, COX-2 selectivity

Synthesis and Preliminary Pharmacological Evaluation of Aminobenzensulfonamides Derivatives of Mefenamic Acid as a Potential Anti-inflammatory Agents

A group of amino derivatives [4-aminobenzenesulfonamide,4-amino-N¹ methylbenzenesulfonamide, or N¹-(4-aminophenylsulfonyl)acetamide] bound to carboxyl group of mefenamic acid a well known nonsteroidal anti-inflammatory drugs (NSAIDs) were designed and synthesized for evaluation as a potential anti-inflammatory agent.  In vivo acute anti-inflammatory activity of the final compounds (9, 10 and 11) was evaluated in rat using egg-white induced edema model of inflammation in a dose equivalent to (7.5mg/Kg) of mefenamic acid. All tested compounds produced a significant reduction in paw edema with respect to the effect of propylene glycol 50% v/v (control group). Moreover, the 4-amino-N-methylbenzenesulfonamide derivative (compound 10) exhibited comparable anti-inflammatory activity to diclofenac (3mg/Kg) at times 180-300 minute with the same onset of action. The results of this study indicate that the incorporation of the 4-aminobenzenesulfonamide pharmacophore and its derivatives in to mefenamic acid maintain its anti-inflammatory activity. Key ward: benzenesulfonamide, anti-inflammatory, paw edema, NSAIDs, mefenamic   aci

Molecular docking study of new sorafenib analogues as platelet-derived growth factor receptor inhibitors for the treatment of cancer

Cancer is a disease triggered by an uncontrolled growth of a group of cells usually from a single cell. Chemotherapy is a common and systematic therapy that involves the use of anticancer drugs also known as chemotherapeutical agents to treat cancer. Tyrosine kinases are a subset of protein kinases that are a family of over 90 enzymes that selectively phosphorylate tyrosine residues in various substrates. Receptors with internal tyrosine kinase activity mediate the actions of several growth factors, differentiation factors, and hormones, resulting in the reproduction and differentiation of the affected cells. In the fight against cancer, the platelet-derived growth factor receptor has emerged as a novel target via inhibition of this receptor resulting in the inhibition of tyrosine kinase cascade. Docking investigations were conducted using the Genetic Optimization for Ligand Docking (GOLD) Suite (v. 5.7.1) from the Cambridge Crystallographic Data Center. A high-definition X-ray crystallography of the platelet-derived growth factor protein [Protein Data Bank (PDB) ID 6JOL] was downloaded from the website PDB with a resolution of 2 A. Compounds II, III, VII, and VIII have greater binding energies than the GOLD standard medication sorafenib, which gives Piecewise Linear Potential (PLP) fitness value (85.3). Other ligands exhibit good inhibitory action and docking scores comparable to that of the reference ligand sorafenib

SYNTHESIS AND PRELIMINARY PHARMACOLOGICAL EVALUATION OF NEW NAPROXEN ANALOGUES HAVING 1, 2, 4-TRIAZOLE-3-THIOL

Objective: The objective of this search was to synthesize a new naproxen analogues having a 1,2,4-triazole-3-thiol heterocyclic ring, and preliminary pharmacological assessment of the anti-inflammatory activity of the synthesized compounds. Methods: The synthesis of naproxen analogues that having 1,2,4-triazole-3-thiol heterocyclic ring occur through esterification of naproxen, and then its reaction with hydrazine hydrate, and carbon disulfide, finally different aromatic aldehydes reacted with triazole derivatives of naproxen containing amino group to produce schiff bases.Results: In vivo acute anti-inflammatory activity of the synthesize compounds (Va-Vd) was evaluated in rats using egg-white induced edema model of inflammation in a dose equivalent to (50 mg/kg) of naproxen. All tested compounds were produced a significant reduction in paw edema with respect to the effect of propylene glycol 50% v/v (control group). Compound Vd produced superior anti-inflammatory activity compared to naproxen.Conclusion: The results obtained in this work give evidence about the valid synthesis of 1,2,4 triazole-3-thiol derivatives of naproxen, which reacted with different aldehydes to yield several schiff bases. The incorporation of benzaldehyde possess para-electron donating group (para-hydroxyl benzaldehyde) will increase the anti-inflammatory activity of naproxen

Molecular modeling, synthesis, and antiproliferative evaluation of new isoxazole ring linked by Schiff bases and azo bond

Lung cancer is the most common malignancy worldwide, with approximately 1.8 million new cases yearly. Cytotoxic drugs are frequently used in cancer treatment. Even though the medicine enhances patients' quality of life, several drawbacks diminish its efficacy. Drug resistance and many disadvantages associated with chemotherapeutic drug side effects continue to be significant factors limiting the efficiency of cancer treatment. This necessitates developing new effective strategies that target tumors with minimal adverse effects. This research aims to overcome these issues by synthesizing a new series of compounds with an isoxazole ring attached by Schiff bases and azo bonds based on molecular docking with the (Genetic Optimization of Ligand Docking) program and estimating the pharmacokinetic properties with the Swiss ADME. The greatest-fitting compounds were then manufactured and verified by spectral analysis (FT-IR, 1H NMR, and 13C NMR), in vitro MTT assay for assessment of antiproliferative activities against A549 lung cancer cell lines showed that compounds 5a and 5b had an inhibitory concentration half-maximal inhibitory concentration (IC50) (17.34 and 18.32 μM), respectively, which was significantly lower than the inhibitory concentration of erlotinib (IC50 = 25.06 μM)

ISOLATION, QUANTIFICATION, AND IDENTIFICATION OF ROSMARINIC ACID, GAS CHROMATOGRAPHY-MASS SPECTROMETRY ANALYSIS OF ESSENTIAL OIL, CYTOTOXIC EFFECT, AND ANTIMICROBIAL INVESTIGATION OF ROSMARINUS OFFICINALIS LEAVES.

Objective: Rosmarinus officinalis L. is an aromatic perennial herb with fragrant evergreen needle-like leaves, and it is member species of Lamiaceae family raised from Mediterranean region. The aims of the study were isolation, quantification, and identification of rosmarinic acid of R. officinalis leaves and essential oil analysis using various chromatographic and spectroscopic methods, and also cytotoxic and antibacterial investigation against different species of bacteria.Methods: It was isolated by preparative HPLC and preparative TLC, and then it was determined by HPTLC. The identification and the structural elucidation of isolated rosmarinic acid were performed by H-nuclear magnetic resonance, electrospray ionization mass spectrometry (MS), infrared, and ultraviolet. Essential oil was analyzed by Gas Chromatography/Mass.Results: Results highlighted that rosmarinic acid content was 0.9% and the oil content was 1.8%, and R. officinalis chemotypes of Iraqi rosemary oil were camphor 23.04%, 1, 8-cineole 14.01%, and terpinen-4-ol 13.8%. The rosemary chemotype characterized as a high concentration of terpinen- 4-ol and good inhibition effect of rosemary methanolic extract against different species bacteria: Enterococcus faecalis, Staphylococcus saprophyticus, Acinetobacter baumannii, and Proteus mirabilis.Conclusions: The plant has a good content of rosemary phytochemicals and antibacterial effect, so the plantation of rosemary in Iraq has been successes. These isolated compounds are a suitable candidate for further clinical and pharmacological study