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.

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, molecular modeling, and biological evaluation of sulfanilamide-imines derivatives as potential anticancer agents.

A series of sulfanilamide Schiff base derivatives (1 to 15) have been designed as potential antitubulin agents depending on the chemical structures of combretastatine A-4 and isoquinoline sulfamate (antimitotic agents under investigation). The designed compounds were synthesized by microwave chemical synthesis, their purity was confirmed by melting point and HPLC and chemical structures were determined by FT-IR, UV, and 1H and 13C-NMR spectroscopic techniques. The synthesized compounds have been docked in the colchicine binding site of ß-tubulin using molecular modeling programs and the antitumor activities were screened on human breast and lung cancer cells by cell counting assay. Some tested compounds showed potent and selective activity against breast cancer (MCF-7) with IC50 range of 90 to 166 µM. With regarding broad-spectrum activity, compounds 4, 8, and 13 have shown potent antitumor activity against human breast and human lung cells with IC50 range of 96 to 140 µM. The obtained results suggest that the sulfanilamide Schiff base derivatives might potentially constitute an interesting novel class of anticancer agents, which deserve further studies.