Crystal and Molecular Structures of the Free Base and the Monohydrochloride Salt of the Antileukemic Agent Glyoxal bis(Amidinohydrazone) [`Glyoxal bis(Guanylhydrazone)’]

Abstract

The first study on the crystal and molecular structures of basic forms of bis(amidinohydrazones) is reported. The structures of the free base and the monohydrochloride salt of the antileukemic agent glyoxal bis(amidinohydrazone) (GBG) were determined by single crystal X-ray diffraction and were refined to R-values of 0.038 and 0.040, respectively. These structures are of special interest because recent results indicate that, in contrast to previous assumptions, the free base may be the actual antileukemic form of bis(amidinohydrazones) and that the monocation form is the predominant species of antileukemic bis(amidinohydrazones) at physiological conditions. In the crystals of the free base as well as in those of the monohydrochloride salt, GBG was found to exist solely in the all-trans configuration of the chain and to consist of one of the three possible geometrical isomers only. In the solid state, GBG free base consists solely of the endiamine tautomer instead of the 'classical’ carboximidamide tautomer, as does also the non-protonated part of GBG monocation in the monohydrochloride salt. Proton NMR measurements indicated that the free base consists of the endiamine tautomer also in dimethyl sulfoxide solution. In the solid state, both of the compounds studied consist of stacks of planes. In the case of the free base, the stacks are crisscross to each other. The distance between the mean planes of the molecules or the monocations is approximately 3.5 Å. The crystals of the monohydrochloride salt contain one molecule of water per each GBG monocation. In both compounds studied, the molecules in the crystals are held together by very extensive hydrogen bond networks and by the interaction of delocalized π-electrons. The crystal of C4H10N8 is monoclinic, space group C2/c with a = 15.874(6), b = 6.972(4), c = 7.8l3(5)Å, β = 90.34(4)° and Z = 4. The crystal of C4H13N8OC1 is monoclinic, space group P21/n with α = 7.010(3), b = 22.307(9), c = 7.028(3)Å, β = 66.33(3)° and Ζ = 4.

Geometrical Isomerism in Guanabenz Free Base: Synthesis, Characterization, Crystal Structure, and Theoretical Studies

“…Although guanabenz is marketed in its monoprotonated form, its free base ( 2 ) cannot be ignored since the available literature on the biological activity of guanabenz and other guanylhydrazone hydrochloride suggested the existence of a considerable portion (∼16%) of free base at physiological temperature (∼37 °C) and pH (7.4). , A few studies were reported on the structural aspects of the free base of guanabenz which includes (i) conformational analysis of both monoprotonated as well as free base of guanabenz, the single crystal X-ray diffraction analysis of E -isomer guanabenz (its details are not available in CCDC); (ii) the experimental and quantum chemical studies on guanabenz to understand prototropic tautomerism. , Recently, we have investigated the tautomerism, , isomerism, , and medicinal applications of azines and concluded that guanylhydrazones exist preferentially in their azine tautomeric state with E -geometry across CN, which was evidenced by analyzing the crystal structures.…”

Azine-Hydrazone Tautomerism of Guanylhydrazones: Evidence for the Preference Toward the Azine Tautomer

“…30 Only a few studies have paid attention to the structure and tautomeric preferences of guanylhydrazones. These studies include (i) the crystal and molecular structure of the free base of the antileukemic agent glyoxal bis (amidinohydrazones), 31 (ii) the crystal and conformational analysis of guanabenz (GBZ) free base, 32 (iii) the structure of guanylhydrazones derived from aromatic aldehydes (NMR, 33,34 X-ray 34 ), and (iv) the crystal structure of 2-(1-phenylethylideneamino)guanidine. 35 All these studies reported the presence of azine (2,3-diaza-1,3-butadiene) tautomer (A) in solution as well as in the solid state.…”

“…The free base of guanylhydrazones cannot be ignored since the available literature on the biological activity of guanylhydrazone hydrochloride suggested the existence of considerable proportion (∼16%) of free base at physiological temperature (37 °C) and pH (7.4). , Moreover, in many reports, wherein the enzymatic activity of the guanylhydrazones is reported, the inhibitory action of these compounds was interpreted with the help of molecular modeling studies. , For example, Qian et al reported guanylhydrazones as anticancer agents targeting tubulin, and during molecular docking studies, they have used hydrazone tautomer instead of azine tautomer as a neutral ligand . Recently, NSC109555, the sole lead chemotype from HTS of 100 000 compounds has been reported as Chk2 inhibitor. − Molecular modeling studies were carried out to predict the binding pose, in which case the hydrazone tautomer as a neutral ligand was considered rather than the azine tautomer .…”

Crystal and Molecular Structure of Aminoguanidine Sulphate, an Important Enzyme Inhibitor and Starting Material of Drug Syntheses

“…Also many other types of com pounds prepared from aminoguanidine have im portant pharm a cological and other applications [10][11]. An excellent detailed review has recently appeared on the chemistry and pharmacology of [8,[17][18][19][20][21][22][23][24][25][26][27][28][29], and also this has created an interest in the structure of am inoguanidine itself. We have there fore now synthesized am inoguanidine sulphate, CN 4H 82+.…”