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

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.

Antimalarial drugs. 40. Folate antagonists. 12. Antimalarial and antibacterial effects of 2,4-diamino-6-[(aralkyl and alicyclic)thio-, sulfinyl-, and sulfonyl]quinazolines

“…The pale yellow crystals were collected and dried to give 2.0 g (71%) of 2,4-diamino-6-(cyclohexylthio)quinazoline (10), mp 190-192 °C with preliminary softening. Procedure V. A mixture of 1.0 g (0.0032 mol) of 6-chloro-5-[(p-chlorobenzyl)thio]anthranilonitrile (7), 0.75 g (0.0065 mol) of chloroformamidine hydrochloride,8 and 4.0 g of dimethyl sulfone was heated for 1 h in an oil bath that had been preheated to 160 °C. The dark solution was poured into water and the resulting cloudy solution was warmed on the steam bath and made basic with 50% sodium hydroxide.…”

“…Many 2,4-diaminoquinazoline antifolates have been demonstrated to possess strong antimalarial properties against sensitive and drug-resistant lines of Plasmodium berghei in mice, P. gallinaceum in chicks, and P. cynomolgi and P. knowlesi in rhesus monkeys.3,4 Among the most potent are nitrosoamino]quinazoline (lb), and 2,4-diamino-6-[ (3,4dichlorobenzyl)methylamino]quinazoline (Ic).1,3-6 However, antimalarial activity of oxygen bioisosteres, exemplified by 2,4-diamino-6-[(p-chlorobenzyl)oxy]quinazoline (II), was greatly reduced. 7 Interestingly, extrusion of the methylene bridge of II restored antimalarial activity. Thus 5,6-dichloro-2-nitrobenzonitrile (Vb) with the appropriate aralkyl or alicyclic thiopseudourea hydrohalide IV in ethanol, using potassium hydroxide as an acid scavenger, produced the corresponding 2-nitro-5-[(aralkyl or alicyclic)thio]benzonitrile VI (1-5, Table I) in 13-67% yield (procedure I).…”

A Novel Method of Synthesis of 2,4-Diamino-6-arylmethylquinazolines Using Palladium(0)-Catalyzed Organozinc Chemistry

“…Although there are a number of examples in the literature of lipophilic DHFR inhibitors in which the fused 2,4-diaminopyrimidine ring system and the aryl side chain are separated by a short O or S bridge, as in 5 and 6, 12,13 the only quinazoline antifolates described to date in which this bridge is CH 2 are the 5,6,7,8-tetrahydro derivatives 7. 14 In the present paper, we report a novel and remarkably straightforward method of synthesis of analogues of 7 in which the B-ring is aromatic.…”

Synthesis and evaluation of 6-arylacetamido-2,4-diaminoquinazolines and related compounds as folic acid antagonists

“…The addition of a second methylene on the opposite side of the amide linkage produces a significantly less inhibitory compound, 27. Conversely, the arylacetamido configuration (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) led to a group of compounds containing some remarkably effective inhibitors. In fact, several of these are as potent as any nonclassical quinazolines evaluated thus far in this laboratory.12 That compounds of this type are superior inhibitors compared with their benzamidomethyl counterparts is fortified by the fact that 2 and 5 are approximately threefold more inhibitory than their isomers 28 and 29, while 8 is some 20-fold more effective than 30.…”