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  • BAPTA-AM br Acknowledgements Thanks are due

    2019-07-11


    Acknowledgements Thanks are due to Science and Technology Development Fund – Egypt for the Research Support Technology Development Grant (RSTDG) no. 12626. Our deep thanks and gratitude is also extended to National Cancer Institute (NCI), Bethesda, Maryland, USA for performing the anticancer evaluation of the new compounds in this study.
    Introduction Malaria is one BAPTA-AM of the most disturbing infectious diseases in the world, due to their high mortality and morbidity. The protozoan parasite Plasmodium falciparum (P. falciparum) is responsible for their occurrence. It has been estimated that around 212 million people get infected in subtropical and tropical countries and 429,000 deaths occur annually by malarial infection. To add to the problem, malaria parasites have acquired resistance against many drugs causing serious problem. We do observe today, a dramatic increase in serious infections due to microorganisms resistant to multiple antimicrobial agents and these have become a problem of great concern.2, 3 To overcome the threat of malarial infection, there is an imperative need for development of new drugs with divergent and unique structures and possibly with a different mechanism of action from that of the existing drugs. Also, recent studies have demonstrated that amino BAPTA-AM changes within P. falciparum dihydrofolate reductase (pf-DHFR) are associated with drug failures. Hence DHFR enzyme has been shown to be reliable and the best target to design new antimalarial drugs. Thus, the need for the discovery of new lead structures and novel chemical entities which will act as antimalarial and antimicrobial agents becomes more relevant. Heterocyclic compounds particularly those with oxygen, nitrogen and sulphur atoms have been identified to have the most comprehensive spectrum of biological activities. Further, benzothiazole are highly important scaffolds in bioorganic and medicinal chemistry with application in drug discovery. This core has shown numerous biological activities such as anticancer,6, 7, 8, 9 antiHIV, antioxidant, anticonvulsant, trypanocidal agent, antitumor,13, 14, 15, 16 antimicrobial, COX inhibitor, hypoglycemic, antidiabetic, antituberculosis,6, 21 antiurease and inhibitor ofα-glucosidase. There are also some well-known drugs such as ethoxzolamide (glaucoma, ulcers and as a diuretic), riluzole (anticonvulsant), pramipexole (Parkinson\'s disease), pharminox and phortress (antitumor) having benzothiazole moiety. Because of their various biological activities such as antimicrobial,24, 25, 26 antitubercular,27, 28, 29 antiHIV anticancer, antitumor, antiinflammatory, analgesic and anticonvulsing,32, 33 compounds with Schiff base moiety are of great interest. Consequently, Schiff bases with benzothiazole moiety are expected to be good pharmaceutical agents. The aim of the study is to develop new heterocyclic compounds as therapeutic agents; accordingly we synthesized and characterized benzothiazole analogues having five member and six member (benzene) rings. This was done to study the effect of the ring size and substituent in the ring on the efficacy of the biological activity. The pharmacokinetic parameters of compounds J 1-J 10 were evaluated. Also, in vitro antimicrobial activity on different pathogenic bacterial and fungal strains, cytotoxicity and genotoxicity on Schizosaccharomyces pombe (S. pombe) cells on cellular level were investigated. The fission yeast S. pombeis an important model organism for the study of eukaryotic molecular and cellular biology. As eukaryotes, these yeasts can be used to study processes that are conserved from yeast to humans but are absent from bacteria, such as organelle biogenesis and cytoskeletal organization or to study mechanisms such as transcription, translation and DNA replication, in which the eukaryotic components and processes are significantly different from those of their bacterial counterparts. The data of antimicrobial activity were correlated with molecular orbital calculations using PM6 and density functional theory (DFT) methods. The importance of DFT calculation to explain biological activity has been demonstrated in a recent publication. In addition, the antimalarial activity of compounds J 1-J 10 were evaluated on P. falciparum strain. In silico molecular docking of active compounds J 1, J 2, J 3, J 5 and J 6 was performed on wild-type Plasmodium falciparum dihydrofolate reductase-thymidylate synthase (pfdhfr-ts) complex (PDB ID: 4DPD) and their in vitro DHFR enzyme inhibition activity was also studied.