Abdul Gbaj

Structure-based design, synthesis, molecular docking, and biological activities of 2-(3-benzoylphenyl) propanoic acid derivatives as dual mechanism drugs

Purpose: 2-(3-benzoyl phenyl)propanohydroxamic acid (2) and 2-{3-[(hydroxyimino)(phenyl)methyl]phenyl}propanoic acid (3) were synthesized from non-steroidal anti-inflammatory drug, ketoprofen as dual-mechanism drugs. Materials and Methods: Structures of the synthesized compounds were established by IR, 1H NMR, and mass spectroscopy. Both compounds were screened for their anti-inflammatory activity in rat paw edema model and in vitro antitumor activity against 60 human tumor cell lines. Flexible ligand docking studies were performed with different matrix metalloproteinases and cyclooxygenases to gain an insight into the structural preferences for their inhibition. Results: Compound (2) proved out to be more potent than ketoprofen in rat paw edema model. Both compounds showed moderate anticancer activity ranging from 1% to 23% inhibition of growth in 38 cell lines of 8 tumor subpanels at 10 μM concentration in a single dose experiment. Hydroxamic acid analogue was found to be more potent than ketoximic analogue in terms of its antitumor activity. Conclusion: Analysis of docking results together with experimental findings provide a good explanation for the biological activities associated with synthesized compounds which may be fruitful in designing dual-target-directed drugs that may inhibit cyclooxygenases and MMPs for the treatment of cancer.

Ester Prodrugs of Ketoprofen: Synthesis, In Vitro Stability, In Vivo Biological Evaluation and In Silico Comparative Docking Studies Against COX-1 and COX-2.

Prompted by the ineptness of the currently used non-steroidal antiinflammatory drugs (NSAIDs) to control gastric mucosal and renal adverse reactions, several ester prodrugs of ketoprofen were synthesized and characterized by IR, 1H NMR and mass spectral data. Physicochemical properties such as aqueous solubility, octanol-water partition coefficient log P, chemical stability and enzymatic hydrolysis of the synthesized molecules have been studied to assess their potential as prodrugs. The obtained results confirmed that all ester prodrugs are chemically stable, possess increased lipophilicity compared to their parent compounds and converted to the active drugs in vivo. All of the tested ester prodrugs exhibited marked anti-inflammatory activity ranging from 91.8% to 113.3% in comparison with the parent drug, ketoprofen. A mutual prodrug obtained from two antiinflammatory molecules, ketoprofen and salicylic acid has been noted to potentiate the activity making it most active molecule of the series. The ulcerogenic index of the ester prodrugs was significantly lower than the parent drug, ketoprofen. Comparative docking studies against X-ray crystal structures of COX-1 and COX-2 further provided understanding of their interaction with the cyclooxygenases that will facilitate design of better inhibitors (or prodrugs) with sufficient specificity for COX-2 against COX-1. The study offers an innovative strategy for finding a molecule with safer therapeutic profile for longterm treatment of inflammatory diseases.

Design, Synthesis and Biological Evaluation of Some Triazole Schiff’s Base Derivatives as Potential Antitubercular Agents

Background: Tuberculosis (TB) is the second important cause of death worldwide caused by a bacterium called Mycobacterium tuberculosis. There is a need to find and develop new Anti-TB medications that are effective, inexpensive and suitable with human immunodeficiency virus and other anti-TB drugs used in many countries and mainly the developing countries where the disease is widespread. These drugs must be designed to shorten treatment time and to be active against resistant forms of the mycobacteria that will help to increase the patients compliance. A key compound which could be used as a lead to meet these requirements, is the thiolactomycin (TLM). This antibiotic which is naturally available has an ability to treat M. tuberculosis by inhibiting condensing enzymes called FAS II (mtFabH, KasA and KasB) which are related to biosynthesis of mycolic acid. Methods: Our main aims are to design and synthesize analogues of TLM as new lead molecules which could be a possible anti–TB candidate. To overcome the synthetic challenges associated with preparing the chiral TLM analogues; we synthesized and investigated a series of triazole analogues as inhibitors of KasA enzyme and the whole cell Mycobacteria. A series of twelve compounds were synthesized, purified and fully characterized using several spectroscopic techniques. Molecular modelling studies for our synthesised compounds were achieved by using a modelling program called AutoDock 4.2 utilising rigid docking. Results: Our results indicate that analogues of TLM show a good activity as compared to TLM. Conclusion: The activity obtained for the synthesized compounds against Mycobacteria tuberculosis indicate that the synthesised compounds 1, 2, 6 and 9 are pharmacologically active as they restrained the growth of the Mycobacteria bacteria.

Intercalation of Rhodamine B into Calf Thymus DNA in presence and absence of olive leaf extract: A fluorescence study

Aqueous olive leaf extract (AOLE) of the Mediterranean tree Olea europaea is stated to have several therapeutic properties including: antifungal, antimicrobial, hypotensive and hypoglycemic actions as well as to use in treatment of some cancer cases as breast, skin and pancreatic cancers. Experimentally, the olive leaf extract is capable to protect nuclear calf thymus and human genomic DNA in vitro to Rhodamine B toxicity. Thus, this study was aimed to evaluate the protective effect of AOLE against toxic DNA damage induced by Rhodamine B using different techniques as UV−VIS Spectroscopy and fluorometry. Genomic DNA was used in a concentration of 75µg/ ml. DNA was extracted from peripheral lymphocytes of anticoagulated blood (EDTA) samples by Proteinase K digestion and phenol/chloroform extraction. Dried leaves of Olea europaea (from West part of Libya) were grinded with distilled water; the resulting aqueous solution was then filtered and used. The protective effect of the AOLE was evaluated for its ability to decrease the amount of Rhodamine B available for binding with double stranded DNA. Thus, DNA resulted in a significant decrease in fluorescence intensity of Rhodamine B. Comparing to control samples, pre- and post-treatment with AOLE, significantly attenuated the binding ability of Rhodamine B to the DNA (p<0.01). Treatment with 5g/15 ml of AOLE was enough to prevent Rhodamine B toxicity to the DNA. The cytoprotective and antioxidant properties were detected in AOLE by a fluorescence method. The antioxidant activity of AOLE was evaluated using the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay and the IC50 was 65±2.3μg/ml. In conclusion, this study suggests that AOLE induced a genoprotective effect by increasing the antioxidant capacity and the chemical interaction between Rhodamine B and constituents of AOLE.

Antimicrobial Evaluation of Novel Metals Complexes of n- Isonicotinamido-2-hydroxy-5-methoxybenzalaldimine

Objective: The appearance of resistant bacteria reduces the efficiency of antimicrobial therapies, thereby increasing the need for more efficient drugs for infections treatment. Many studies have shown an enhance in antimicrobial activity after the interaction of many agents with metal ions. Complexes of the metal ions with ligands which are polydentate have been the theme of demanding research as they have interesting spectral, magnetic properties and a miscellaneous spectrum of biological activities. Methods: New isoniazid based compounds and their transition metal complexes (cobalt (II), copper (II), nickel (II) and zinc (II)) were produced using microwave synthesis technique. The All compounds which were synthesized (free ligand and their metal complexes) were fully characterized by many spectroscopic techniques (FT-IR spectra, UV/visible electronic spectra, mass spectra and 13C NMR and 1H NMR spectra). In addition, CHN, XRFA, AAS merged with other spectroscopic data were utilized to allocate the precise ligand to metal ratio and geometry. The synthesized ligands and their complexes were tested for in vitro antimicrobial activity against Candida albicans (ATCC 10231), Aspergillus niger (ATCC 16404), Escherichia coli (ATCC 25922), and Staphylococcus aureus (ATCC 29213) by using agar-well diffusion. Results: Based on analytical and spectroscopic findings, the ligands proceed as a coordinate and monoanionic tridentate throughout phenolic oxygen, azomethine nitrogen, and carbonyl oxygen. New complexes of nisonicotinamido- 2-hydroxy-5-methoxy benzalaldimine with Cu(II), Co(II) and Zn(II), having a formula of the type [M (L) 2].nH2O, (M = Co(II), n = 1.5; Zn(II), n = 0; Cu(II), n = 6) and with Ni(II), featuring a formula of the type [M (L) (H2O)] (ac).nH2O, (M = Ni(II), n = 0, ac = CH3COO¯) were obtained. Accordingly, octahedral geometries were determined to Zinc(II), Cobalt(II) and Copper(II) complexes and geometry of the tetrahedral was allocate to the Ni(II) complex. Conclusion: Biological findings indicate that complexation may increase or decrease the antimicrobial activity of some complexes. This could be endorsed to an increase of complexes lipophilicity in comparison to the parent ligand.

Evaluation the Anti-Inflammatory Activity of Some Eastern Libyan Medicinal Plants

Four Libyan medicinal plants Olea Europaea (Oleacea), Cistus Incanus (Cistaceae), Launaea Residifolia (Asteraceae) , Cistus Parviflorus ,Lam(Cistaceae) were collected from EL –jabal EL-akhdar eastern Libya in April 2010 .after identified the plants were extracted using microwave technique by three solvents (methanol-ethyl acetate –hexane ) .these plants were studied for anti-inflammatory activity using carrageenan induced mice odema model. The plant extracts of different solvents were administered at dose 250 mg /kg of the body weight intraperitoneally. among these extracts, Cistus Parviflorus ,Lam extract especially methanolic and ethyl acetate extracts gave the most significant % inhibition of inflammation after 3 hr (57.4±1.9 65.5±2.5 respectively) this effect was better than standard reference aspirin (55.1±1.9)