Please use this identifier to cite or link to this item: http://prr.hec.gov.pk/jspui/handle/123456789/20795
Title: Design and Synthesis of New Anti-Bacterial Agents Targeting Multidrug Resistant Escherichia coli and Staphylococcus aureus
Authors: Bashir, Muhammad Arslan
Keywords: Physical Sciences
Chemistry
Issue Date: 2019
Publisher: University of Karachi, Karachi.
Abstract: Multidrug Resistance (MDR) is the capacity which allows pathogens (fungi, viruses, bacteria, and parasites) to resist anti-microbial agents.There are two mechanisms of multidrug resistance in bacteria. Firstly, within a single cell, these bacteria may build up a variety of genes, each one of them is coded for a single drug for the development of resistance; secondly, extruding out drugs through efflux pump proteins. Development of new anti-microbial agents is the biggest challenge of 21st century with the emergence of multidrug resistance. Currently we are facing the biggest threat of a post-anti-biotic era with limited capacity to fight against microbial infections. During the current studies, we have synthesized several new compounds which have anti-bacterial activity against drug resistant bacteria, as S. aureus and E. coli. For this purpose, we used readily available cheap starting materials with known anti-bacterial potential, as templates for further modifications. The current research work comprises synthesis of tyramine and quinolines derivatives, and evaluation of theirin vitro biological activities. Different spectroscopic techniques were used for identification of synthesized compounds structure such as EI-MS, 1H NMR, HREI-MS, 13C-NMR, and IR spectrophotometer. Rf values were also measured. Chapter-1 gives the general introduction about anti-biotics, history of penicillin and quinolines, multidrug resistance, its causes and control. It also provides the details about Escherichia coli and Staphylococcus aureus.In addition to this explains drug discovery mechanisms, the emergence of new anti-biotics, brief history of tyramine and quinolone as a template molecules, and plan of our research work. Chapter-2 deals with the general introduction of imine functionality, its chemical and medicinal importance. The conventional and ultrasonic synthesis of imine derivatives 19- 43 of tyramine and evaluation of their various bioactivities in vitro are discussed. Twenty five members of the library were synthesized; all compounds were found to be new, except compounds 25, 29, and 37. Compounds 30 and 41 showed a good anti-bacterial activity against resistant starins of E. coli respectively. Only compound 43 showed excellent anti-bacterial activity against resistant strains of S. aureus. Compounds 23, 30, and 35-37 were found to potent inhibition ofα-glucosidase, as compared to the standard. Compounds 36 and 38 demonstrated a weak potential against protein glycation when compared to standard rutin. Compounds 19, 20, 21, 23, 24, 25, 26, 27, 28, and 34 Summary xiii showed good to moderate in vitro urease inhibition activity as compared to the standard thiourea. Only compound 21 showed a weak activity against parasite leishmaniasis in vitro. All the compounds were inactive against DPP-IV enzyme inhibition assay, and all compounds were found to be non-cytotoxic. Chapter-3 gives the general introduction of amides, synthesis of amide derivatives of tyramine, and their purification and characterization. All synthesized compounds 50-63 were then evaluated for their biological activities, including anti-bacterial and other activities. All compounds of the library were found to be new except compounds 50, 57, 58, 59, and 63. All compounds were found inactive against E. coli and S. aureus (resistant strains). Compounds 50, 51, 52, 55, 60, 62, and 63 were found to have several hundred folds better inhibitory potential against α-glucosidase. Acarbose was used as a standard drug. All the compounds 50-63 were inactive against protein glycation, urease inhibition, anti-leishmanial, and DPP-IV activities. None of the compounds was found to be cytotoxic. Chapter-4 describes thiourea, synthesis of thiourea derivatives of tyramine, and their purification and characterization. All synthesized compounds 64-83 were evaluated against various biological activities, such as anti-bacterial activity. All compounds of the library were found to be known, except compounds 65, 67, 68, 69, 70, 71, 76, and 81. All compounds were found inactive against the resistant strains of E. coli. Compounds 69, 72, 73, 74, 76, 80, and 81 showed excellent to good activity against the resistant Summary xiv strains of S. aureus. All compounds were found several hundred folds more potent against α-glucosidase enzyme as compared to the standard, except compounds 64, 65, 66, 76, and 81. Compounds69, 74, and 79 have many folds better inhibitory potential against urease, when compared to the standard thiourea. All the synthetic compounds, except 68, 77,and 80 showed many fold better inhibitory potential against β glucuronidase, as compared to the standard, saccaric acid 1,4-lactone. All synthesized compounds 64-83 were found to be inactive against DPP-IV enzyme and DPPH radical scavenging activity. All the compounds were found to be non-cytotoxic except compound 67. Chapter-5 gives the general introduction of quinoline, synthesis of ester derivatives of quinoline, and their purification and characterization. All synthesized compounds 85-108 were evaluated against various biological activities, such as anti-bacterial activity. Only seven compounds of the library were found to be new (86, 90, 91, 92, 97, 101, and 105). Compounds 88, 90, 91, 102, 106, and 107 were found to have good anti-bacterial activity against the resistant strains of S. aureus. Compounds 85, 89, 91, 92, 95, 101, 103, 104,105, and 106 showed a hundred fold better potential against α-glucosidase, as compared to the standard. Compounds 85-92, 94, 95, 100, 101, 103, 105, and 106 showed good to moderately anti-leishmanial, as compared to the standard pentamidine. Compounds 85, 95, 97,and 100 showed many fold better in vitro immunomodulatory activity and compounds 89 and 91 showed good activity when compared to ibuprofen as a standard drug. All compounds 85-108 of the library were found to be inactive against urease inhibitory, DPP-IV enzyme inhibition, and DPPH radical scavenging activities. All compounds 85-108 were found to be non-cytotoxic. Chapter-6 describes the microscopic investigations on the selected compounds by analysis of morphology and membrane roughness through SEM and AFM at molecular Summary xv level of selected compounds. Three compounds 43, 73, and 90 selected from the synthesized libraries showed a potent activity against S. aureus by destroying the cell wall of the microbe, and producing deep ruptures. Control cells of EMRSA-16, EMRSA 17, MRSA-252, and of the Pakistani drug resistant clinical isolates displayed a consistent grape-like morphology. After treatment with the selected compounds, reduction, swelling, and eventually bursting of the membrane were observed. Many chipped and fractured cells were also seen. These observations indicated that the selected compounds possess a highly destructive/ inhibitory activity towards the MDR cells, and thus are ideal candidates for the development of clinically useful anti-bacterial agents
Gov't Doc #: 26013
URI: http://prr.hec.gov.pk/jspui/handle/123456789/20795
Appears in Collections:PhD Thesis of All Public / Private Sector Universities / DAIs.

Files in This Item:
File Description SizeFormat 
Muhammad Arslan Bashir 2019 chemistry uok karachi.pdfphd.Thesis4.72 MBAdobe PDFView/Open


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.