I= DESIGN AND SYNTHESIS OF SOME NEW DERIVATIVES OF ISONIPECOTAMIDE AS POTENTIAL THERAPEUTIC AGENTS
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Title of Thesis
DESIGN AND SYNTHESIS OF SOME NEW DERIVATIVES OF ISONIPECOTAMIDE AS POTENTIAL THERAPEUTIC AGENTS

Author(s)
Shamim Akhtar
Institute/University/Department Details
University of Karachi/ Department of Pharmaceutical Chemistry
Session
2003
Subject
Pharmacy
Number of Pages
273
Keywords (Extracted from title, table of contents and abstract of thesis)
isonipecotamide, antibacterial activity, morphinoids, opioids, piperidine nucleus, phenyl nucleus, nipecotamide, tridecanoyl

Abstract
Molecular modification of simple and complex chemical entities may lead to biologically active compounds. Different types of approaches are made to derive such compounds, which exhibit selective pharmacological effects. Morphinoids and related compounds exhibited potent analgesic activity but they also proved to be narcotic in nature. In order to avoid addictive property attempts are made to modify the molecule in various ways. It has been observed that in almost all the different types of opioids, piperidine nucleus along with a phenyl nucleus is an essential part. Synthetic analogues of pethidine led to the modification of pethidine molecule, which is composed of piperidine as basic skeletal entity

In order to assess the biological efficacy of isonipecotamide, which also contains a piperidine nucleus, attempts are made to prepare various derivatives of nipecotamide and isonipecotamide

During the course of present work several derivatives of Isonipecotamide are synthesized and their biological activities such as analgesic, anti-inflammatory, behavioral, cardiovascular, cytotoxic, antibacterial and antifungal are assessed as described in the experimental section

These activities are attributed to the quaternary compounds prepared when isonipecotamide is reacted with substituted phenacyl halides The structures of these compounds are confirmed by 1HNMR, EIMS, UV and IR spectral analysis

Different biological activities are performed using different techniques such as analgesic activity is tested by tail immersion method, In order to study neurochemical changes, the level of various parameters like DOPAC, DCA, HVA, 5HT and 5HIAA are assessed. Effects of some of the compounds on behavior of rats are observed by open field method

The comparison of Isonipecotamide derivatives with that of nipecotamide is also included to prove the significance of these compounds, so that a distinct observation can be made with to the position of carboxamide in piperidine nucleus

The results are interesting as:

1. Among all the compounds, the phenacyl derivatives of isonipecotamide substituted at the 4th position of phenyl ring are found more active than the parent compound except in neuro studies. Substitution of hydroxyl groups at 3rd and 4th positions in compound (II) exhibited pronounced effects on the release of biogenic amines

2. Other than phenacyl derivatives, two compounds, i.e., phenylpropyl and tride-canoyl derivatives of isonipecotamide displayed significant effects when tested for different biological activities. Despite of the structural differences between 3,4-dihydroxy and propylphenyl derivatives, both the compounds showed almost similar effects in cases of blood pressure analgesic activity and release of neurochemical transmitters

3. Promising cytotoxic and broad spectrum antibacterial effects expressed by tridecanoyl of isonipecotamide (XVI) may be attributed to the long chain of alkyl group. However the use of any compound in medicine or food science will require safety and toxicity issues to be addressed. The significance of the results may lead to the conclusion that the present work would offer much information and knowledge for the progress of drug design in future

Download Full Thesis
2153.83 KB
S. No. Chapter Title of the Chapters Page Size (KB)
1 0 Contents 0
89.32 KB
2 1 Introduction 1
274.34 KB
  1.1 Aims and objective 35
3 2 Experimental 36
247.01 KB
  2.1 Synthesis 37
  2.2 Methodology of pharmacological evaluation 58
4 3 Results and discussion/General discussion 69
1359.55 KB
  3.1 Analegesic activity 70
  3.2 Anti-inflammatory activity 86
  3.3 Behavioral studies 103
  3.4 Neurochemcial estimations 118
  3.5 Effect on mean arterial blood pressure (MABP) and Heart rate 190
  3.6 Cytotoxic activity (brine-shrimp bioassay ) 199
  3.7 Antibacterial activity 204
  3.8 Antifungal activity (In vitro bioassay ) 211
5 4 Conclusion 215
29.88 KB
6 5 References 218
355.3 KB
7 6 Appendices/List of tables 260
125.04 KB
  6.1 List of figures 263
  6.2 List of synthesized compounds 269
  6.3 List of Abbreviations 270
  6.4 List of research publications 272