X-ray crystallography has been responsible for results. leading to fundamental and important structural concepts. Each

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Baldric Gregory Smith
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1 Chapter 9 CONCLUSION AND THE SCOPE FOR FUTURE STUDIES X-ray crystallography has been responsible for results leading to fundamental and important structural concepts. Each crystal structure reveals something about the molecular function. These structural concepts have contributed significantly to computer-aided molecular design, rational drug design, etc. ' The thesis deals with the crystal and molecular structures of some heterocyclic compounds of biological interest and their complexes. Derivatives of nucleobases and their analogues are widely used as drugs. For example, acyclovir (2-amino-l,9-dihydro-9- [(2-hydroxyethoxy)methyl]-6H-purin-6-one] is an antiviral agent. 5-fluorouracil is an antineoplastic drug. AZT(3'-azido-3'- deoxythymidine) is used in the treatment of AIDS. Crystallographic studies on a large number of such compounds will enable the scientists to correlate the structure and drug activity. The conformations of these drugs can be compared with related structures retrieved from Cambridge Structural Data Base. For many drugs, their receptor proteins are also known. Crystal structures of these proteins can also be retrieved from Brookhaven Protein Data Bank(PDB). Moreover, crystal structures of many protein-drug complexes are also available with the Brookhaven Protein Data Bank. These structures and their interacting patterns are very useful for computational studies 73 c

2 of drugs and drug-receptor recognition. The combined results obtained from X-ray studies, NMR studies and computational techniques contibute towards rational drug design. A N-9 SUBSTITUTED ADENINES: Arprinocid (9-(2-chloro-6-fluorobenzyDadenine), a N9 substituted adenine is a coccidiostat. The crystal structures of arprinocid hydrobromide hemihydrate and arprinocid diperchlorate have been investigated. The orientation of the phenyl ring with respect to adenine plane in these structures have been compared with related structures. N-6 SUBSTITUTED ADENINES: X-ray crystallographic investigations of N -benzyladenine hydrochloride, N -benzyladenine hydrobromide, cupric bromide complex of N -benzyladenine (aquadibromobis(n -benzyladeninium)- -copper(ii) bromide) and a cupric chloride complex of kinetin (dichlorobis(n -furfuryladeninium)copper(ii) chloride) have been carried out. N -benzyladenine and kinetin are cytokinins(plant growth regulators). In these cytokinins, the plane of the substituent makes a dihedral angle of about 90" with the adenine plane. In the cytokinins reported in the thesis, N(3) of adenine is protonated whereas in adenine systems, normally N(l) is the preferred site of protonation on addition of acids. There is a large scope for further study regarding the effect of substituent on protonation sites. This aspect can be studied by solving crystal structures of a series of N -substituted adenines and evaluating their biological activity. The problem can also be 73 d

3 further probed by theoretical and computational techniques. Already computational work on N -benzyladenine system has been started in our laboratory. SUBSTITUTED PYRIMIDINES: Trimethoprim(2,4-diamino-5-(3',4',5'-trimethoxybenzyl)- -pyrimidine) is a widely used drug (antibacterial). It is also a model for substituted pyrimidine. Crystal structures of trimethoprim sulphate trihydrate, trimethoprim perchlorate and trimethoprim formate have been investigated to understand the conformation and hydrogen bonding patterns of protonated trimethoprim moiety in a variety of crystalline and molecular environments. Hydrogen bonding interactions observed in these small structures are directly relevant to the hydrogen bonding patterns observed when the drug interacts with the target enzyme, dihydro folate reductase (DHPR). In such interactions, water molecules also play vital roles. The crucial role played by such "invariant" water molecules 73 in crystal structures of proteins and protein-drug complexes is hotly pursued due to the availability of accurate data obtained by synchrotron radiation. The knowledge on hydrogen bonding patterns gained by small molecule studies will be relevant for understanding hydrogen bonding patterns occuring in biomacromolecular systems. The crystal structure of trimethoprim formate serves as a model for carboxylate-pyrimidine interactions. In this crystal structure, there is a fork like hydrogen bonding interaction between the formate anion and the trimethoprim cation. This interaction 73e

4 occurs in DHFR-TMP complexes. This type of fork like interaction can occur in protein-nucleic acid recognition also. For example, the side chain carboxylate group of a protein can interact with the pyrimidine of the nucleic acid in a similar fashion.,.. 73,121 ' POLYMORPHISM AND TAUTOMERISM IN DRUGS: Polymorphism in drugs is directly related to medical application like bioavailability. Trimethoprim is a well known drug. Recently, a new polymorph of trimethoprim and its crystal structure have also been reported. Tautomerism in drugs is 80 also very important. Understanding polymorphism and tautomerism will be useful for designing drugs with desired physico-chemical properties. In the thesis, crystal structure of benzthiazide (6-chloro-3-t[(phenylmethyl)thiojmethyl]-4H-l,2,4- -benzothiadiazine-7-sulfonamide 1,1-dioxide), an antihypertensive agent has been described. The drug exists as the 4H tautomer rather than 2H tautomer. Recently, in our laboratory, the crystal structure of a new polymorph of benzthiazide has also been determined. Further work on polymorphism and tautomerism in drugs is in progress. METAL-DRUG INTERACTIONS: Studies of metal-drug interactions are of current interest. 122 Metal ions can modulate drug activity. For understanding the metal-drug interactions at the molecular level, crystal structures of metal complexes of drugs are investigated. In the thesis, crystal structures of cobalt and cadmium complexes of 73f

5 thiabendazole have been reported. Thiabendazole (2-(4-thiazolyl) -IH-benzimidazole) is an anthelmintic. It is also used as a fungicide in agriculture. In both the metal complexes investigated, the metal binds to benzimidazole nitrogen and the thiazole nitrogen. The sulphur of the thiazole group is not involved in metal binding. It has been planned to synthesise more such metal complexes so that i) their metal binding modes can be investigated. ii) Drug activities of the metal complexes can be evaluated and compared with the free drug. Thus the work presented in the thesis offers a wide scope for future studies- computational studies of these molecules, investigation of related molecules etc.. Such endeavour will lead to further knowledge which will be helpful in the design of more drugs and agrochemicals. 73?-

Chapter VII Introduction

Chapter VII Introduction 41 Chapter VII Hydrogen bonding patterns in co-crystal structures of 2-amino-4, 6-dimethylpyrimidine- terephthalic acid (2/1) [1], 2-amino-4, 6-dimethylpyrimidine-succinic acid (1/1) [2], 2- amino-4,6-dimethoxypyrimidine-succinic