Crystal structure of creatininium 5-(2,4-dinitrophenyl)-1,3-dimethylbarbiturate monohydrate: a potential anticonvulsant agent

The title molecular salt exhibits anticonvulsant and hypnotic activities. In the crystal, the 5-(2,4-dinitrophenyl)-N,N-dimethylbarbiturate anion is linked to the creatininium cation by N—H⋯O hydrogen bonds, forming sheets parallel to the ab plane.


Chemical context
Creatinine is a breakdown product of creatine phosphate during metabolic activity in living systems (Ueda, 1964). Creatinine exists in both the amino and the imino tautomeric forms. Due to the presence of various groups, such as CH 3 , CH 2 , NH, NH 2 and C O, it can form C-HÁ Á ÁO, N-HÁ Á ÁO and O-HÁ Á ÁO hydrogen bonds with other molecules. Barbiturates are pyrimidine derivatives which exhibit their action by modulating the ion channels. Pyrimidine and its derivatives have been shown to be effective medications (Brown, 1962;Gauthier et al., 1963;Shorvon, 2004;Jain et al., 2006;Tripathi, 2009). In this context, a number of pharmacologically active molecular salts with different barbiturate entities and cationic counter parts have been described (see for example : Rajamani & Kalaivani, 2015;Gomathi & Kalaivani, 2015). Herein, we describe the synthesis and crystal structure of the title molecular salt, which has been shown to exhibit anticonvulsant and hypnotic activities.

Structural commentary
The structure of the title molecular salt is illustrated in Fig. 1. The bond lengths and bond angles are normal and comparable with those observed in related barbiturates (Sridevi & Kalaivani, 2012;Gunaseelan & Doraisamyraja, 2014). The fivemembered ring of the creatininium (2-amino-1-methyl-4-oxo-4,5-dihydro-1H-imidazol-3-ium) cation is essentially planar with an r.m.s. deviation of 0.015 Å . In the anion, the 2,4-di-nitrophenyl ring is inclined to the mean plane of the pyrimidine ring (r.m.s. deviation = 0.37 Å ) by 43.24 (8) . The nitro group ortho with respect to ring junction is inclined to the benzene ring to which it is attached by 37.6 (2) , while the nitro group para with respect to the ring junction is inclined to the benzene ring by 7.4 (3) . The different dihedral angles imply that though two nitro groups are involved in delocalizing the negative charge on the oxygen atom of barbiturate ion, the para nitro group is more effective than the ortho nitro group.

Supramolecular features
In the crystal, the anion and cation are linked via N-HÁ Á ÁO hydrogen bonds, forming sheets parallel to the ab plane ( Fig. 2 and Table 1). The sheets are linked via O-HÁ Á ÁO hydrogen bonds involving the water molecule, forming a three-dimensional framework ( Fig. 3  The molecular structure of the title molecular salt, with atom labelling. Displacement ellipsoids are drawn at the 40% probability level.

Biological activity
Epilepsy (convulsion) is one of the most common neurodegenerative disorder affecting at least 50 million people worldwide. Brain dysfunction due to different causes leads to epilepsy (Fisher et al., 2005). Barbiturates have a pyrimidone ring system. From their introduction into clinical practice at the beginning of the 20th century until recent years, they have occupied a vital place in the pharmacopoeia as CNS drugs (Yadav, 2004). The anticonvulsant activity of the synthesized barbiturate has been measured by employing the Maximal Electro Shock method (Kulkarni, 1999). In the present investigation, the title molecular salt reduces the clonus phase of convulsion to a greater extent than other phases of convulsion (flexion, extension and stupor) even at low dosage (25 mg kg À1 ) and hence may be used in the future for controlling myoclonic epilepsy of infants. The therapeutic dose induces hypnosis in albino mice. Acute toxicity tests have also been carried out according to OECD guidelines on albino mice (LD 50 >1000 mg kg À1 ; falls under class 4). The animals did not show any indication of behavioural changes after testing with the title molecular salt. The high safety margin reveals its significance as a potential anticonvulsant agent.

Synthesis and crystallization
Dinitrochlorobenzene (2.02 g, 0.01 mol) was dissolved in 20 ml of absolute alcohol. To this 1.56 g (0.01mol) of 1,3-dimethylbarbituric acid was added and the temperature of the mixture was raised to 323 K. To this mixture 1.13 g (0.01 mol) of creatinine in 20 ml of absolute alcohol was added. This mixture was shaken well for 2-5 h and kept as such at 298 K for 2 d. On standing, a maroon-red-coloured solid came out from the solution. The solid was ground to a fine powder, washed with absolute alcohol and dried with ether and then recrystallized from absolute alcohol. The solution was left to stand and maroon-red block-shaped crystals were obtained after two weeks. The crystals were harvested and air dried (yield: 80%; m.p. 483 K).

Refinement
Crystal data, data collection and structure refinement details are summarized in A view along the a axis of the crystal packing of the title molecular salt. The hydrogen bonds are shown as dashed lines (Table 1). The C-bound H atoms have been omitted for clarity, and the water molecules are shown as red balls.