Microwave-assisted synthesis of new benzimidazole derivatives with lipase inhibition activity

The most commonly used modern anthelmintics include the benzimidazoles, the nicotinic agonists. praziquantel, triclabendazole and the macrocyclic lactones. These drugs interfere with target sites that are either unique to the parasite or differ in their structural features from those of the homologous counterpart present in the vertebrate host. The benzimidazoles exert their effect by binding selectively and with high affinity to the beta-subunit of helminth microtubule protein. The target site of the nicotinic agonists (e.g. levamisole, tetrahydropyrimidines) is a pharmacologically distinct nicotinic acetylcholine receptor channel in nematodes. The macrocyclic lactones (e.g. ivermectin, moxidectin) act as agonists of a family of invertebrate-specific inhibitory chloride channels that are activated by glutamic acid. The primary mode of action of other important anthelmintics (e.g. praziquantel, triclabendazole) is unknown. Anthelmintic resistance is wide-spread and a serious threat to effective control of helminth infections, especially in the veterinary area. The biochemical and genetic mechanisms underlying anthelmintic resistance are not well understood, but appear to be complex and vary among different helminth species and even isolates. The major mechanisms helminths use to acquire drug resistance appear to be through receptor loss or decrease of the target site affinity for the drug. Knowledge on the mechanisms of drug action and resistance may be exploitable for the development of new drugs and may provide information on ways to overcome parasite resistance, respectively.

A series of 2-methylaminobenzimidazole derivatives (1-11) were synthesized by the reaction of 2-(chloromethyl)-1H-benzimidazole derivatives with primary aromatic amines. All these compounds were characterized by IR, 1H NMR, 13C NMR, GC-MS and elemental analysis. The newly synthesized compounds were screened for analgesic and anti-inflammatory activities on acetic acid induced writhing in mice and carrageenan induced paw oedema in rats. Compounds (7) and (2) showed a potent analgesic (89% at 100 mg/kg b.w) and anti-inflammatory (100% at 100 mg/kg b.w) activities compared with standard drug Nimesulide (100% at 50 mg/kg b.w) respectively. The other compounds showed good analgesic and anti-inflammatory activities.