and the quinine equiv Q (the ratio of the SD90 of quinine-HC1 to the SD90 of the test substance under comparable exptl conditions). 2,4-Diamino-6- [(benzyl)aminb] pyrido [2,3-d]pyrimidine (Via) and 2 ,4-diamino-6-[(3,4-dichlorobenzyl)amino] pyrido [2,3-d] pyrimidine (VIb) lacked significant antimalarial effects at daily doses of 325 and 171 mg/kg, respectively, and were therefore <20 times as potent as the corresponding quinazoline analog 2,4-diamino-6-[(3,4-dichlorobenzyl)amino] quinazoline (la).2 2,4-Diamino-6-[(3,4-dichlorobenzyl)nitrosamino] pyrido [2,3-d]

Eleven 2,4-diamino-6-(heterocyclic)quinazolines (VI) were prepared by condensing 5-chloro-2-nitrobenzonitrile (III) with the appropriate saturated heterocycle to give the corresponding 5-(heterocyclic)-2nitrobenzonitriles (IV) (24-94%), followed by SnCl2-2H20 reduction to the 2-amino-5-(heterocyclic)benzonitriles (V) (51-85%) and cyclization to VI (6-71%) with chloroformamidine HC1 or cyanoguanidine. The reaction of 2,4;6-triaminoquinazoline (33) with 2,5-diethoxytetrahydrofuran, acetonylacetone, phthalic anhydride, and , '-dibromoxylene afforded 2,4-diamino-6-(pyrrol-l-yl)quinazoline (34), 2,4-

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.

2 Various4‐diamino‐6‐(benzyl and pyridyhnethyl)‐5,6,7,8‐tetrahydropyrido(4,3‐d]pyrimidines (IX) have been synthesized for antimalarial and antibacterial evaluation. Alkylation of 4‐amino‐3‐cyano‐1,2,5,6‐tetrahydropyridine (VI) with the requisite α‐chlorotoluene or picolyl chloride in 2‐butanone afforded the corresponding 4‐amino‐3‐eyano‐1‐(benzyl and pyridvlmethyl)‐1,2,5,6‐tetraliydropyridines (VIII) (16–73%), which were cyclized to the pyrido[4,3‐d]pyrimidines (IX) utilizing guanidine carbonate in dimethylformamide. Alternatively, VI was condensed with guanidine carbonate in ethyl cellosolve to give 2,4‐diamino‐5,6,7,8‐tetrahydropyrido[4,3‐d]‐pyrimidine (VII) (52%), which upon treatment with the appropriate α‐ehlorotoluene in dimethyllormamide gave other 2,4‐diamino‐6‐benzyl‐5,6,7,8‐tetrahydropyrido[4,3‐d]pyrimidines (IX) (26–27%). Kight compounds were active orally against Plasmodium berghei in mice at doses ranging from 3.9 to 125 mg./kg./day for 6 days (0.6 to 19 times as potent as quinine hydrochloride), while three compounds displayed activity when administered in a single subcutaneous dose of 640 mg./kg. Four substances exhibited in vitro activity against Streptococcus faecalis (MGH‐2), normal (UC‐76) and drug‐resistant (S18713) Staphylococcus aureus, and Streptococcus pyogenes ((1203), with MIC's ranging from > 0.25 to 10 μg./ml. Data on the inhibitory effects of various pyrido[4,3‐d]pyrimidines against Streptococcus faecalis R (S. faecium var. durans, ATCC 8043), S. faecalis A (aminopterin, metholrexate‐resistant), and Lactobacillus plantarum (ATCC 8014) is summarized.

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