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  • br Results and discussion br Conclusion Analogues

    2020-02-21


    Results and discussion
    Conclusion Analogues of 1,2,4-triazole and 1,3,4-oxadiazole have been designed, synthesized and characterized. To avoid late stage failure, it is important to study the preliminary pharmacokinetic parameters. The results of pharmacokinetic data suggested that, all molecules have tendency to be considered as drugs. So in vitro antimicrobial, cytotoxicity and genotoxicity on S. pombe Brassinolide and antimalarial on P. falciparum of these analogues have been investigated. The molecules were subjected to DFT and PM6 calculations to explain the anti-bacterial activity. It was found that the antibacterial activity could be correlated to energies of the LUMO and maximum LUMO electron density. All the compounds possessed moderate to good inhibitory potency against bacterial strains and did not show any anti-fungal activities. The compounds SS 4, SS 5 and SS 7-SS 10 were found to possess maximum toxicity against S. pombe cells at cellular level. All the compounds S 1-SS 10 showed smearing type pattern on agarose gel due to toxic nature of these compounds. The anti-malarial activity of these compounds were studied. The compounds SS 2 (two p-hydroxy benzene groups), SS 3 (two m-nitrobenzene groups) and SS 4 (two p-chlorobenzene groups) attached to 1,2,4-triazole ring and SS 9 (p-chlorobenzene) attached to 1,3,4-oxadiazole ring were found to be potent against P. falciparum strain. The in silico docking showed that the potent molecules synthesized and the standard drugs inhibit the enzyme P. falciparum dihydrofolate reductase occupying the active binding pocket with great ease. The antimalarial efficacy was further proved by in vitro DHFR enzyme inhibition study. Hence, this study identified new structural type antibacterial and antimalarial agents which could be used as lead molecules for further research and development of antibacterial and antimalarial agents.
    Conflict of interest
    Acknowledgement The authors thank the authorities of Charotar University of Science & Technology (CHARUSAT), Changa, Gujarat, India for providing the facilities to carry out this investigation. They also thank Dr. Devendra Tiwari, School of Chemistry, University of Bristol, Untied Kingdom for his help in the molecular orbital study. Mr. Parth Thakor is thankful to DST INSPIRE program for the fellowship.
    Introduction The enzyme dihydrofolate reductase (DHFR) exhibits an important role in DNA synthetic pathway. As known DHFR catalyzes the reduction of 7,8-dihydrofolate or folate to 5,6,7,8-tetrahydrofolate using nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor, so it has been recognized for a long time as an attractive target for drug action. Inhibitors of DHFR have shown an important role in the chemotherapy [1], [2] neoplastic diseases [3], [4], bacterial infections [5] malaria [6] and rheumatoid arthritis [7]. The classical inhibitor of DHFR is the methotrexate (MTX), which shows certain effectivity in the treatment of cancer. But, it has a hydrophilic character, which prevents its distribution into cells of various body tissues by diffusions, such as lung and brain [3]. In the last years, many Quinazoline derivatives with anticancer activity have been studied as inhibitors of DHFR, many studies of QSAR and molecular modifications have been implemented to design some new potent DHFR inhibitors, with a lipophilic character, but the results are not very satisfying [8], For this purpose, a series of some potent DHFR inhibitors: 7,8-dialkyl-1,3-diaminopyrrolo-[3,2-f] Quinazolines with a lipophilic character have been designed and reported by Kuyper et al. [9]. They are relatively small and compact but potent inhibitors of fungal and human DHFR. In the recent years, two QSAR-2D and 3D studies on this series have previously developed with lipophilic and CoMFA descriptors [10]. So, it would be worthwhile to extend these with all available data nowadays: QSAR-3D (CoMFA, CoMSIA) and molecular docking studies to better understand the in vitro activity of the studied compounds, than to get a deep vision, which allows us to design some new lipophilic potent DHFR inhibitors, in order to avoid the MTX limitation.