Design, syntheses, characterization, and evaluation of 2-substituted-1,3-bis(1-naphthylmethyl)-imidazolidine derivatives in search of safer nonsteroidal anti-inflammatory drugs

Abstract

Background: 1,2,3-trisubstituted imidazolidines are reported to have better anti-inflammatory activity than the reference drug indomethacin. Similarly, naphthalene nucleus plays a significant role in the drug design. Nabumetone and naproxen are naphthalene nucleus containing anti-inflammatory drugs available in the market. There are also reports that compounds having two naphthalene rings incorporated with a heterocyclic nucleus have good medicinal value. Based on these reports it was planned to synthesize hybrid compounds containing two naphthalene rings with imidazolidine nucleus. Aim: To obtain potent compounds having anti-inflammatory and analgesic activities with reduced gastrointestinal side effects. Materials and Methods: The reaction scheme includes the reaction between 1-naphthaldehyde with ethylenediamine to obtain diSchiff′s base (1) Reduction of this diSchiff′s base with NaBH 4 gave tetrahydrodiSchiff′s base (2) Further cyclization of 2 with appropriate aldehyde in the presence of ethanol formed 2-substituted-1,3-bis(1-naphthylmethyl)-imidazolidine derivatives (3a-n). The structures of these compounds were established on the basis of spectral data. All these compounds were tested for their anti-inflammatory, analgesic, ulcerogenic, and lipid peroxidation activities. Results and Discussion: The tested compounds (3a-n) showed anti-inflammatory activity ranging between 27.61% and 53.43%. The compound 3h showed the highest activity of 53.43% and 3n showed 53.02% inhibition at 20 mg/kg dose in rats compared with the standard drug indomethacin which showed 61.45% inhibition at the same dose. It was encouraging to note that both the compounds showed reduced ulcerogenic activity (less than half) compared to the standard drug indomethacin.