Crystallographic Investigations of Heterocyclic Compounds of Pharmacological Interest

Abstract

Single-crystal X-ray structure determinations are reported for the following heterocyclic compounds: (1) 3,4-dihydro-4-phenylimino- 1,2,3-benzotriazine (DIPB) (2) 4,7-dihydro-6,7-diphenyl-7-ethoxy (1,2,4] triazolo [5,1-c] triazine: (DETT) (3) 4,6-diamino-p-chlorophenyl- 1,2-dihydro-s-triazine (cycloguanil) hyorochloride (CGT) (4) 2,4-diaminoquinazoline (DAQ) and (5) 3-hydroxy-4-oxy- 1,2,3-benzotriazine. The refinement of hydrogen atom parameters for CGT from neutron data was also undertaken. The medicinal interest in each of the above compounds is surveyed. CGT and DA@ are inhibitors of dihydrofolate reductase (DHFR). The biochemistry of DHFR inhibition is reviewed, along with a detailed comparison of geometrical parameters for DHFR inhibitors which have been investigated crystallographically. Clinical investigations of the entimalarial activity of CST have been reviewed. The position of protonation in CGT was unambiguously identified in a neutron Fourier synthesis enc found to conform to the pattern observed in all other known DHFR inhibitors. with the object of investigating possible cis-trans isomerism, CNDO/Z molecular orbital calculations have peen carried out for DIPB and two other crystallographically investigated 4-anilino substituted 1,2,3-benzotriazines. The calculated energies indicated that it is steric rather than electronic considerations which govern the isomeric form adopted. A survey of the crystallographic software available at the University of Aston and the University of Manchester Regional Computer Centres is reported along with the development of programs for four-circle diffractometer data reduction, display of unit cell contents for structures of monoclinic and higher symmetry, molecular geometry calculations and the contouring and peak searching of Fourier syntheses.