Synthesis and antimalarial properties of 2,4‐diamino‐6‐[(aryl)thio, sulfinyl, and sulfonyl]pyrido[3,2‐d]pyrimidines

The synthesis and antimalarial activity of a series of 2,4‐diamino‐6‐[(aryl)thio, sulfinyl and sulfonyl]pyrido‐[3,2‐d]pyrimidines is described. Nitration of 2,6‐dichloropyridine provided the 3‐nitro derivative which was converted to 6‐chloro‐3‐nitro‐2‐pyridinecarbonitrile (V) with cuprous cyanide. Condensation of an aryl thiol with V gave the 6‐arylthiopyridines VI which were reduced with iron in hydrochloric acid and condensed with chloroformamidine to give the 6‐arylthiopyrido[3,2‐d]pyrimidin‐2,4‐diamines X. Alternatively V was reduced to the amine VIII condensed with chloroformamidine and the resulting 6‐chloropyrido[3,2‐d]pyrimidine (IX) was treated with an arylthiol. Oxidation of X provided sulfinyl and sulfonyl analogs.