Synthesis and analgesic activity of novel pyrimidine derivatives of coumarin moiety.

Abstract

The investigation of compounds able to treat both acute and chronic pain is challenging in pharmaceutical research (1). Pain is in fact a very important problem present in 90% of diseases, from the simple back pain to pain associated with different forms of cancer. The classical therapies for pain treatment are mainly the non-steroidal anti-inflammatory drugs (NSAIDs) and opiates, whose lead compounds, acetylsalicylic acid and morphine, respectively, were isolated in 19th century. (2) NSAIDs show side effects such as gastrointestinal irritation and lesions, renal toxicity and inhibition of platelet aggregation, while the use of opioids is limited to severe pain because of adverse secondary reactions as respiratory depression, dependence, sedation, and constipation. (3, 4) Hence, there is always a need for those drugs which have improved analgesic activity and less adverse effects. Nitrogen containing heterocycles, such as pyrimidine, are promising structural moieties for drug design. Pyrimidine derivatives form a component in a number of useful drugs and are associated with many biological, pharmaceutical and therapeutical activities (5). Condensed pyrimidine derivatives have been reported as anti-microbial(6), analgesic, anti-viral, anti-inflammatory (7), anti-HIV (8), antitubercular (9), anti-tumor (10), anti-neoplastic (11), antimalarial (12), diuretic (13) and cardiovascular agents(14). Pyrimidine compounds are also used as hypnotic drugs for the nervous system (15), calcium-sensing receptor antagonists (16) and also for antagonists of the human A2A adenosine receptor (17). Like pyrimidine, coumarin also exhibits diverse biological properties (18, 19). It was envisaged that these two active pharmacophores, if linked together, would generate novel molecular templates which are likely to exhibit interesting biological properties in animal models. The above-cited applications prompted us to synthesize a series of new compounds reported in this article. Owing to the importance, here we have described the synthesis of new pyrimidine derivatives from 3-acetylcoumarins (Scheme 1). The compounds were screened for their in vivo analgesic activity. Thus, we have created new avenues to explore the potent heterocyclic moieties for the pharmacological activities in medicinal chemistry.