Folate antagonists. 5. Antimalarial and antibacterial effects of 2,4‐diamino‐6‐(aryloxy and aralkoxy)quinazoline antimetabolites

Abstract

Abstract 2 Various4‐diamino‐6‐(phenoxy, naphthyloxy, and phenalkoxy)quinazolines (VIII, XIV) were synthesized for antimalarial and antibacterial evaluation. Treatment of the anion of the requisite phenol or naphthol with 5‐chloro‐2‐nitrobenzonitrile (V) gave the corresponding 2‐nitro‐5‐(phenoxy and naphthyloxy)benzonitriles (VI) (33–78%). Alternatively, alkylation of 5‐hydroxy‐2‐nitrobenzaldehyde (IX) with the appropriate phenalkyl halide afforded the 2‐nitro‐5‐(phenalkoxy)benzaldehydes (X) (27–62%), which were converted to the 2‐nitro‐5‐(phenalkoxy)benzonitriles (XII) via the intermediate oximes XI (62–87% overall). Reduction of the 2‐nitrobenzonitriles (VI, XII) with stannous chloride‐hydrochloric acid provided the corresponding 2‐amino‐5‐(phenoxy, naphthyloxy, and phenalkoxy)benzonitriles (VII, XIII) (30–83%), which upon cyclization with chloroformamidine hydrochloride gave the 2,4‐diaminoquinazolines VIII and XIV (12–85%). Against Plasmodium berghei in mice, eleven compounds were active orally at doses ranging from 6.3 to 174 mg./kg./day for 6 days, while seven substances displayed activity subcutaneously following single doses of 40–640 mg./kg. Fifteen compounds exhibited in vitro antibacterial activity against Streptococcus faecalis (MGH‐2), normal (UC‐76) and drug‐resistant (S18713) Staphylococcus aureus, Escherichia coli (Vogel), and Shigella sonnei (C‐10) with MIC's ranging from < 0.25 to 20 μg./ml. (gradient plate). Data on the inhibitory effects of representative compounds against Streptococcus faecalis R ( S. faecium var. durans), S. faecalis A (amino‐pterin, methotrexate‐resistant), and Lactobacillus plantarum are presented, and overall structure‐activity relationships are discussed.