Chemotherapeutic agents. XII [1]. Synthesis of Pyrimidines and Fused Pyrimidines as leishmanicides and herbicides

Various bicyclic ( 2 , 3 ) and tricyclic ( 4 , 5 ) heterocycles were prepared by the reaction of 1a , c with dihaloalkanes and polynitrohalobenzene separately. Electrophilic substitution on 1a–c with different alkyl halides yielded mono and dialkyl pyrimidiens ( 6–20 ). Nucleophilic substitution reactions on 18 and 21 with amine and hydrazine separately yielded 22–31 , 21a , b and 41c . Reaction of 25a with ethyl ethoxymethylenecyanoacetate and chloroacetyl chloride separately provided bicyclic compounds 32 and 33 . Condensation-cyclization of 25a with formic, acetic and nitrous acid separately yielded 34a , b and 35 . Reaction of 26a with ethylthiocylycolate and thiourea separately provided 36a and 39 . The latter was alkylated with methyl iodide to 40 . An attempt to cyclize 29a and 30a with thionyl chloride provided bicyclic compounds 37a , b and an uncyclic product 38 . Some of the compounds were screened for leishmanicidal and herbicidal activities and a few of them exhibited significant activity. Leishmaniasis is considered to be one of the most devastating diseases and is ominous to tropical countries. The high toxicity of leishmanicidal drugs in current use, aroused considerable interest to develop new safer and effective chemotherapeutic agents. The only drug pyrimethamine [2] is the representative of pyrimidine derivatives, known as leishmanicides but low order of activity at high dose failed to retain in the clinic. Based on our past experiences in rational designing of leishmanicidal pyrimidine analogs, incorporation of levamisole pharmacophore either in flexible or rigid forms is indispensable for potential activity [1,3] against visceral leishmaniasis. These observations induced an impetus to synthesize pyrimidine analogs as potential leishmanicides.