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.

Date of Award	1979
Original language	English
Awarding Institution	Aston University