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.

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.

Quinone bioreductive prodrugs as delivery agents.

Quinone bioreductive prodrugs were developed to target the hypoxic or the reductase- rich population of solid tumours. The mechanism of their selective activation is based on their ability to convert the quinone sub-structure to their activated semiquinone or hydroquinone species affording the active species. Recent studies on their biochemical activation process have resulted in their development as delivery agents that can effectively release a potent (but not necessarily a cytotoxic) agent under hypoxic/reductive conditions. This technology platform is currently being used to design/identify, and synthesise novel quinone bioreductive delivery agents to target cancer and other diseases where hypoxia and/or reductive enzymes play a major pathophysiological role.

3-substituted-5-aziridinyl-1-methylindole-4,7-diones as NQO1-directed antitumour agents: mechanism of activation and cytotoxicity in vitro.

Indolequinone agents are a unique class of bioreductive cytotoxins that can function as dual substrates for both one- and two-electron reductases. This endows them with the potential to be either hypoxia-selective cytotoxins or NAD(P)H:quinone oxidoreductase 1 (NQO1)-directed prodrugs, respectively. We have studied the structure-activity relationships of four novel indolequinone analogues with regard to one- and/or two-electron activation. Single-electron metabolism was achieved by exposing the human carcinoma cell line T47D to each agent under hypoxic conditions, whilst concerted two-electron metabolism was assessed by stably expressing the cDNA for human NQO1 in a cloned cell line of T47D. The C-3 and C-5 positions of the indolequinone nucleus were modified to manipulate reactivity of the reduction products and the four prodrugs were identified as NQO1 substrates of varying specificity. Two of the four prodrugs, in which both C-3 and C-5 groups remained functional, proved to be NQO1-directed cytotoxins with selectivity ratios of 60- to 80-fold in the T47D (WT) versus the NQO1 overexpressing T47D cells. They also retained selectivity as hypoxic cytotoxins with oxic/hypoxic ratios of 20- to 22-fold. Replacement of the C-3 hydroxymethyl leaving group with an aldehyde group ablated all selectivity in air and hypoxia in both cell lines. Addition of a 2-methyl group on the C-5 aziridinyl group to introduce steric hinderance reduced but did not abolish NQO1-dependent metabolism. However, it enhanced single-electron metabolism-dependent DNA cross-linking in a manner that was independent of cytotoxicity. These data demonstrate that subtle structure-activity relationship exists for different cellular reductases and under certain circumstances distinct forms of DNA damage can arise, the cytotoxic consequences of which can vary. This study identifies a candidate indolequinone analogue for further development as a dual hypoxia and NQO1-directed prodrug.