Synthesis, X-ray crystallography and antimicrobial activity of 2-cyanoguanidinophenytoin

Abstract

The optimized synthesis of [5-oxo-4,4-diphenylimidazolidin-2-ylidene]cyanamide, which is known as 2-cyanoguanidinophenytoin (CNG-DPH) (3), and (imidazo[4,5-d]imidazole-2,5-diylidine)dicyanamide (4) has been reported in the present work. Furthermore, new Mannich bases derived from CNG-DPH were synthesized via its reaction with formaldehyde and using the corresponding amines, piperidine (base 5), and morpholine (base 6). Also, the antimicrobial activity and X-ray crystal structures for CNG-DPH and their Mannich bases were studied. The bases 3 and 6 crystallized in a monoclinic system; the crystal structure of 3 containing four molecules in the unit cell with a P21/c space group. The unit cell of 6 has eight molecules with a C2/c space group. The inter and intra hydrogen bond contacts packed and stabilized both of the structures. The morpholine ring of base 6 demonstrated a distinctive chair configuration. Mannich bases 5 and 6 showed promising antimicrobial effects. base 4 has a greater percentage for in vitro cytotoxicity (IC50) against normal cells, whereas 3 has the lowest ratio.

X‐Ray Crystallography and Antimicrobial Activity of Synthetic Cyanoguanidinophenytoin Cocrystals

“…The cocrystal was extremely linked through an N−H−N hydrogen bond between N16 at the cyanide group and H47 at N8 of the piperidine molecule ( see Table 2&Figure 3a), which is in line with the reported cocrystals containing a piperidine ring [35] . The published standard bond distance and the molecular geometry were generally in close accord [36,37] and also consistent with what was reported about 2‐cyanoguanidinophenytoin and piperidine crystal structures [34,35] . Ring puckering analysis revealed chair stereochemistry at the 6‐membered piperidine ring (N8/C17/C25/C27/C18/C22), as seen in Figures 2&3b [38–40] …”

“…From all mentioned above and in continuation of our previous works, [25–34] here in the present work we prepared a novel series of 1 : 1 cocrystals of cyanoguanidinophenytoin CNG‐DPH 1 with some diverse primary, secondary, and tertiary aliphatic amines (Table 1), taking into account the study of their potential antimicrobial activities and X‐ray crystallography structure for cocrystal 10 .…”

“…[35] The published standard bond distance and the molecular geometry were generally in close accord [36,37] and also consistent with what was reported about 2cyanoguanidinophenytoin and piperidine crystal structures. [34,35] Ring puckering analysis revealed chair stereochemistry at the 6membered piperidine ring (N8/C17/C25/C27/C18/C22), as seen in Figures 2&3b. [38][39][40] The structures were stabilized by intermolecular forces and hydrogen bonds, which form a three-dimensional parallel network.…”

“…[23] On the other hand, 2-(cyanoimino)-5,5-diphenyl-4imidazolidinone (cyanoguanidinophenytoin, CNG-DPH) (see Figure 1C), whose structure is analogous to that of phenytoin, was previously synthesized from the reaction of benzil with cyanoguanidine, and both of them acted as the most potent anticonvulsant activity. [24] From all mentioned above and in continuation of our previous works, [25][26][27][28][29][30][31][32][33][34] here in the present work we prepared a novel series of 1 : 1 cocrystals of cyanoguanidinophenytoin CNG-DPH 1 with some diverse primary, secondary, and tertiary aliphatic amines (Table 1), taking into account the study of their potential antimicrobial activities and X-ray crystallography structure for cocrystal 10. The chemical structures of all synthesized cocrystals 3-13 were confirmed based on their spectral data (IR, 1 H, 13 C, Dept-135 NMR), elemental analysis data, and X-ray crystallography.…”

“…Gram-positive bacteria have an outer membrane bounded by layers of peptidoglycan that are many times thicker than those seen in gram-negative bacteria. [43,44] Our previous study for similar 2-cyanoguanidinophenytoin derivatives [34] showed poor antibacterial activity, but when it was connected to another substance in the cocrystals, its antimicrobial efficacy improved on gram-positive. This strongly confirms that the cocrystal form clearly enhanced the biological activity.…”