Proinhibition Of Dihydrofolate Reductase Using Pyrimethamine

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ACKNOWLEDGEMENT

I would take this opportunity to thank my research supervisor, family and friends for their support and guidance without which this research would not have been possible

DECLARATION

I, [type your full first names and surname here], declare that the contents of this dissertation/thesis represent my own unaided work, and that the dissertation/thesis has not previously been submitted for academic examination towards any qualification. Furthermore, it represents my own opinions and not necessarily those of the University (Bardhan, 2001, 467).

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ABSTRACT

Motivation. Malaria is globally recognized as serious problem of public health, mainly in the tropical and subtropical regions of the world. The increase of resistant malarial parasite strains represents the largest obstacle to antimalarial chemotherapy. In this work, we studied chalcone derivatives, because they present wide range of biological activity and a supposed mechanism of action: inhibition of malarial cysteine protease.

Method. QSAR analysis was performed on the series of chalcone derivatives. Various physical-chemical parameters such as hydrophobic, electronic, steric, thermodynamic and structural were calculated using computational package Molecular Modeling Pro 4.0, ChemSite Pro 5.0 and Arguslab 4.0 programs. QSAR models with up to four variables were generated employing multiple linear regression method using BuildQSAR program.

Results. Statistically significant models with R-values 0.931 and 0.958 were obtained. Results obtained show that hydrophobic and steric properties seem to play an important role in the explanation of the activity. Molar refractivity and molecular length have positive contribution to the activity against chloroquine-resistant (W2) Plasmodium Jalciparum strains, while molecular weight against mefloquine-resistant (D6) strains. The results indicated that the activity against W2 and D6 strains is favored if ring A is a width-limited chemical substituent and the limited molecular width of these derivatives can be related with the activity against D6 strain.

Conclusions. The present QSAR study reveal descriptors that may be important in the inhibitory activity of chalcone derivatives on P.falciparum cysteine protease. We obtained two different models against Plasmodium falciparum strains. The models have good capacity to explain the observed values of biological activity, good adjustment level, statistical significance and good predictive capacity.

Keywords. Chalcone derivatives; quantitative structure-activity relationships; QSAR; Plasmodium falciparum. TABLE OF CONTENTS

ABSTRACTIV

CHAPTER 1: INTRODUCTION8

Introduction8

CHAPTER 2: LITERATURE REVIEW13

Plasmodium falciparum13

Background13

Life Cycle of Plasmodium falciparum15

Plasmodium falciparum - Malaria15

Plasmodium falciparum drugs18

Dihydrofolate reductase - DHFR21

Structure-based drug design for DHFR-TS22

What is SBDD22

Choice of Target: TS vs. DHFR24

Future Therapeutics for DHFR-TS25

Case Study27

Methods of CoMFA study30

Analysis of the Case31

CoMFA contour analysis34

Cost Effective Drugs37

CHAPTER 3: METHODOLOGY & EXPERIMENT41

Chemical Data41

Computer Software41

Quantum chemistry QSAR analysis43

QSAR model selection44

CHAPTER 4: RESULTS AND DISCUSSION46

CHAPTER 5: CONCLUSION57

REFERENCES58

CHAPTER 1: INTRODUCTION

Introduction

Malaria is an infection caused by the protozoa of the genus Plasmodium. The man is commonly infected by four species of the parasite, i.e., Plasmodium ovale, P. vivax, P. malariae and P. Jalciparum, the last being the most virulent to humans. These parasites can be introduced in the human organism through the bite of a female Anopheles mosquito, the injection or transfusion of infected blood and through the hypodermic syringes. According to the World Health Organization (WHO), malaria is globally recognized as ...