Synthesis and anti-oomycete activity of novel quinazolin- and benzothiazol-6-yloxyacetamides: Potent aza-analogs and five-ring analogs of quinoline fungicides

Episodes from the Continuous Search for Solutions against Downy Mildew Diseases

“…Amongst several different synthesis directions, during which we varied different parts of 28, [26][27][28] finally it was the fine-tuning of physico-chemical properties of the quinoline portion of 28, resulting in the close analogs 29 and 30, which brought back the potency against the most important oomycetes diseases. [29] The fungicidal activity of all of these compounds is due to their ability to inhibit the fungal tubulin polymerization by binding to the colchicine site, leading to microtubule destabilization (Scheme 4). [30] The synthesis of the quinoline-based broad-spectrum fungicide 28 starts with the Skraup-type ring closure reaction of 4-methoxy-2-methylaniline (31) with 2,2,3-tribromopropanal to deliver the 3-bromoquinoline derivative 32.…”

“…In analogy to the above described synthesis sequence 33 → 28, the hydroxyl function of 39 was then alkylated with methyl 2-chloro-2-(methylsulfanyl)acetate, the ester function of 40 was hydrolytically cleaved and the resulting carboxylic acid 41 converted into the target product 29, which is a quinazoline analog of the quinoline derivative 28 (Scheme 6). [29] For the synthesis of the benzothiazole-based tubulin polymerization inhibitor 30 we chose 2-chloro-4-methoxyaniline (42) as starting material, which could be cyclized to the 2-aminobenzothiazole derivative 43 upon treatment with potassium thiocyanate and bromine. This well-known 2-aminobenzothiazole synthesis proceeds via an ortho-thiocyanatoaniline intermediate, which undergoes ring closure by reaction with bromine.…”

“…The finalization of the synthesis is achieved by using the same last three steps as already applied for the preparation of 28 and 29 in Schemes 5 and 6, which are alkylation of the phenol function to 46, ester saponification to 47 and amide coupling, delivering the benzothiazole analog 30 of the quinoline derivative 28 (Scheme 7). [29] Although several of the quinolin-6-yloxyacetamides such as 28 showed mediocre activity against the foliar diseases potato late blight and grape downy mildew, good in vivo activity against the which the ring nitrogen exactly keeps its position between the two ring carbon atoms bearing the carboxamide function and the piperidine, would be an interesting target. Two small conformationand exit vector-driven changes to this surprisingly inactive molecule, shifting the ring nitrogen to the other ortho-position of the carboxamide function and the removal of the methyl substituent from the amide nitrogen, turned 49 into the highly active analog 51.…”

“…As it turned out, the higher polarity of the quinazoline and benzothiazole analogs of 28, as demonstrated by their lower logP values and the much higher water solubility, resulted in better translation from the in vitro Pythium assay to the in vivo test, especially the quinazolin-6-yloxyacetamide 29, which has an almost 1000-fold increased water solubility compared to the quinoline analog 28, shows excellent efficacy against this devastating seedling-damaging disease (Table 3). [29]…”

Synthesis of Linker Isomers of Quinolin-6-yloxyacetamide Fungicides through Newman–Kwart Rearrangement

“…1 In addition, the replacement of the quinoline core by a quinazoline or a benzothiazole, leading to excellent activity against Pythium ultimum, the causal agent of the take-all disease, has been reported recently. 2 A significant position of the quinolin-6-yloxyacetamide lead compound 1, which so far has never been derivatised, is the oxygen atom that links the quinoline bicycle with the acetamide part. In this paper we describe the synthesis of quinolin-6-ylthioacetamide 2 and quinolin-6-ylpropan-amide 3, in which the oxygen linker of 1 has been replaced by either a sulfur atom or a methylene bridge (Figure 1).…”