Please use this identifier to cite or link to this item: http://prr.hec.gov.pk/jspui/handle/123456789/14973
Title: Synthesis of N-Heterocyclic Carbene Complexes for Medical Applications
Authors: Atif, Muhammad
Keywords: Physical Sciences
Chemistry
Issue Date: 2020
Publisher: University of Agriculture, Faisalabad.
Abstract: Almost of invasive cancers as well as pathogenic microbes are developing resistances to many potent drug analogues. This fact has geared the trend to develop more and more novel or newer synthetic drug candidates in pursuit to timely substitute the traditional ineffective drugs analogues. To contribute in the same, the present work was directed to synthesize newer NHeterocyclic carbene (NHC) compounds for the evaluation of their preliminary bioactivities to consequently present the finding for further biological studies in overcoming their respective avenues of drug resistance. NHC class of compounds was selected in view of their potential to inhibit microbial DNA and oncogenic proteins. The synthesis was made by Nalkylation of imidazole and benzimidazole to produce imidazolium and benzimidazolium salts respectively which were further reacted using In-Situ technique for metallation. The synthesis was confirmed by X-ray crystallography, FT-IR, 1H-NMR and 13C-NMR. For this purpose, N-Heterocyclic compounds of three categorical groups were synthesized which include: (Group-I) silver-N-Heterocyclic carbene (Ag-NHC) complexes and their respective azolium salts, (Group-II) ytterbium-N-Heterocyclic carbene (Yb-NHC) complexes along with their precursor compounds and (Group-III) Se-N-Heterocyclic carbene (Se-NHC) adducts and their respective azolium salts. Azolium salts include imidazolium salts and benzimidazolium salts only. Besides Yb-NHC complexes, all synthetic analogues were subjected to suitable preliminary bioactivities which include anti-cancer, anti-bacterial and anti-fungal studies. Group-I and Group-III were studied were studied in terms of their Invitro anticancer activities through Nuclear Chromatin Condensation by fluorescence microscopy and antiproliferative activity by MTT assay. Anticancer activities of Group-I compounds were assessed in terms of human colorectal cancer (HCT-116), breast cancer (MCF-7) and erythromyeloblastoid leukemia (K-562). And for Group-III compounds both anticancer and antimicrobial studies were directed. For anticancer studies, the binding potential of the test compounds to target proteins in various cancer cell lines was assessed by molecular docking studies of computational analysis. In this way, four cancer cell-lines including murine melanoma cancer cell line (B16F10), rat retinal ganglion cancer cell line (1-8RGC5), cervical cancer cell line (HeLa) and breast cancer cell line (MCF7-1). For antimicrobial studies, durable applications of test compounds on the surface of cotton fabric were accomplished. Firstly, antibacterial activities of the test compounds against Bacillus subtilis (gram-positive) and Escherichia coli (gram-negative) were explored. Then screened analogues of significant antibacterial activities were subjected to antifungal studies while using sAspergillus niger. The study explored that the followed synthetic methodologies for N-alkylation and salt formation, In-situ reaction for metallation were found effective in getting high product yields of studied classes of N-Heterocyclic derivatives. But the adopted transmetallation technique for the synthesis of Yb-N-Heterocyclic Carbene Complexes could not considered successful. For Group-III compounds, molecular docking analysis of bisbenzimidazolium based selenium adducts showed that compound 37 for VEGFA protein; compound 36 and 37 for EGF protein; again 37 for Hif prote in offered highest drug-protein interaction. In context to In-vitro anticancer studies of the same test compounds with lowest inhibitory concentrations were as: 34 (IC50 = 7.17µM) and 37 (IC50 = 4.56µM) for B16F10; BH-C (IC50 = 8.28µM) and BDM-C (IC50 = 9.27µM) for 1-8RGC5; BPE-C (IC50 = 10.36µM) and 37 (IC50 = 16.17µM) for HeLa; and 24 (IC50 = 3.54µM) and 34 (IC50 = 6.14µM) for MCF7-1 cancer cell-line. In antimicrobial study, test compounds, 34 showed promising antimicrobial efficiency on the test fabrics which was 65% against Bacillus subtilis, 73% against Escherichia coli and 45% against Aspergillus niger. On the cytotoxicity assessments Group-I compounds in terms of human colorectal cancer (HCT-116), breast cancer (MCF-7) and erythromyeloblastoid leukemia (K-562) cell lines without molecular docking analysis and their cytotoxicities of silver compounds and their respective bisbenzimidazolium salts showed that all silvercomplexes have been found to exhibit potent anti-cancer activities, while the benzimidazolium salts displayed weaker activity than their corresponding complexes. In particular, symmetrically substituted complex 46 of this group inhibited proliferation of HCT 116 cells in culture at lowest concentrations with the IC50 value of 0.31 µM, which is being ten-fold greater than the inhibitory concentration of 5-flourouracil used. It is speculated from the available data that the increased antiproliferative effects of silver-complexes is associated with cellular apoptosis and cell cycle arrest, as analogous carbene-complexes likely to exert similar activity.
Gov't Doc #: 20275
URI: http://prr.hec.gov.pk/jspui/handle/123456789/14973
Appears in Collections:PhD Thesis of All Public / Private Sector Universities / DAIs.

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