Scaffold hopping approaches for the exploration of herbicidally active compounds inhibiting Acyl-ACP Thioesterase.

BACKGROUND: The sustainable control of weed populations is a significant challenge facing farmers around the world. Although various methods for the control of weeds exist, the use of small molecule herbicides remains the most effective and versatile approach. Striving to find novel herbicides that combat resistant weeds via the targeting of plant specific modes of action (MoAs), we further investigated the bicyclic class of acyl-acyl carrier protein (ACP) thioesterase (FAT) inhibitors in an effort to find safe and efficacious lead candidates. RESULTS: Utilizing scaffold hopping and bioisosteric replacements strategies, we explored new bicyclic inhibitors of FAT. Amongst the investigated compounds we identified new structural motifs that showed promising target affinity coupled with good in vivo efficacy against commercially important weed species. We further studied the structure-activity relationship (SAR) of the novel dihydropyranopyridine structural class which showed promise as a new type of FAT inhibiting herbicides. CONCLUSION: The current work presents how scaffold hopping approaches can be implemented to successfully find novel and efficacious herbicidal structures that can be further optimized for potential use in sustainable agricultural practices. The identified dihydropyranopyridine bicyclic class of herbicides were demonstrated to have in vitro inhibitory activity against the plant specific MoA FAT as well as showing promising control of a variety of weed species, particularly grass weeds in greenhouse trials on levels competitive with commercial standards. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

The (±)-5-Aza[1.0]triblattane Skeleton via Azetine Cycloaddition.

The first synthesis of the 5-aza[1.0]triblattane skeleton was achieved through a [4 + 2] cycloaddition approach using a suitably protected azetine and cyclopentadiene. A series of azetines were synthesized to explore both stability and suitable N-protection. The key step following cycloaddition utilized a noninitiated protonated aminyl radical cyclization to install the final 5-azatriblattane bond, but it was found to be considerably more unstable than the 6-aza isomer under acidic conditions.

9-Azahomocubane.

Homocubane, a highly strained cage hydrocarbon, contains two very different positions for the introduction of a nitrogen atom into the skeleton, e. g., a position 1 exchange results in a tertiary amine whereas position 9 yields a secondary amine. Herein reported is the synthesis of 9-azahomocubane along with associated structural characterization, physical property analysis and chemical reactivity. Not only is 9-azahomocubane readily synthesized, and found to be stable as predicted, the basicity of the secondary amine was observed to be significantly lower than the structurally related azabicyclo[2.2.1]heptane, although similar to 1-azahomocubane.

seco-1-Azacubane-2-carboxylic Acid: Derivative Scope and Comparative Biological Evaluation.

The unusual and sterically constrained amino acid, seco-1-azacubane-2-carboxylic acid, was incorporated into a range of bioactive chemical templates, including enalaprilat, perindoprilat, endomorphin-2 and isoniazid, and subjected to biological testing. The endomorphin-2 derivative displayed increased activity at the δ opioid receptor, but a loss in activity was observed in the other cases, although human normal cell line evaluation suggests limited cytotoxic effects.

seco-1-Azacubane-2-carboxylic acid-Amide Bond Comparison to Proline.

seco-1-Azacubane-2-carboxylic acid, an unusual and sterically constrained amino acid, was found to undergo amide bond formation at both the N- and C-termini using proline based bioactive molecule templates as a concept platform.

1-Azahomocubane.

Highly strained cage hydrocarbons have long stood as fundamental molecules to explore the limits of chemical stability and reactivity, probe physical properties, and more recently as bioactive molecules and in materials discovery. Interestingly, the nitrogenous congeners have attracted much less attention. Previously absent from the literature, azahomocubanes, offer an opportunity to investigate the effects of a nitrogen atom when incorporated into a highly constrained polycyclic environment. Herein disclosed is the synthesis of 1-azahomocubane, accompanied by comprehensive structural characterization, physical property analysis and chemical reactivity. These data support the conclusion that nitrogen is remarkably well tolerated in a highly strained environment.

The (±)-6-Aza[1.0]triblattane Skeleton: Contraction beyond the Wilder-Culberson Ring System.

Synthesis of the 6-aza[1.0]triblattane skeleton and the unexpected construction of the 7-azatetracyclo[4.2.1.02,5.03,7]nonane framework are reported, as inspired by the Wilder-Culberson 1-aza[1.1]triblattane ring system. The key steps to assess the 6-aza[1.0]triblattane include accessing the 1,6-cycloaddition product from reaction of chlorosulfonyl isocyanate with cyclohept-1,3,5-triene followed by intramolecular electrocyclization and aminium radical cyclization.

1,4-Diazacubane crystal structure rectified as piperazinium.

All 21 [n]-azacubanes are proposed by theoreticians to be stable, however, to-date only the synthesis of 1,4-diazacubane has been reported - as a Ni2+ templated Kagome metal organic framework (MOF). Described herein is the structural reassignment of this Kagome MOF on the basis of deducing the precise experimental procedure, and demonstrating that rather than the formation of 1,4-diazacubane, charge is balanced by disordered piperazinium cations across a twelve-fold symmetry site. Furthermore, quantum chemical calculations reveal that 1,4-diazacubane is unlikely to form under the reported conditions due to unfavorable enthalpies for select hypothetical reactions leading to such a product. This significant structure correction upholds the unconquered synthesis status quo of azacubane.

The cubane paradigm in bioactive molecule discovery: further scope, limitations and the cyclooctatetraene complement.

The cubane phenyl ring bioisostere paradigm was further explored in an extensive study covering a wide range of pharmaceutical and agrochemical templates, which included antibiotics (cefaclor, penicillin G) and antihistamine (diphenhydramine), a smooth muscle relaxant (alverine), an anaesthetic (ketamine), an agrochemical instecticide (triflumuron), an antiparasitic (benznidazole) and an anticancer agent (tamibarotene). This investigation highlights the scope and limitations of incorporating cubane into bioactive molecule discovery, both in terms of synthetic compatibility and physical property matching. Cubane maintained bioisosterism in the case of the Chagas disease antiparasitic benznidazole, although it was less active in the case of the anticancer agent (tamibarotenne). Application of the cyclooctatetraene (COT) (bio)motif complement was found to optimize benznidazole relative to the benzene parent, and augmented anticancer activity relative to the cubane analogue in the case of tamibarotene. Like all bioisosteres, scaffolds and biomotifs, however, there are limitations (e.g. synthetic implementation), and these have been specifically highlighted herein using failed examples. A summary of all templates prepared to date by our group that were biologically evaluated strongly supports the concept that cubane is a valuable tool in bioactive molecule discovery and COT is a viable complement.

Cyclooctatetraene: A Bioactive Cubane Paradigm Complement.

Cubane was recently validated as a phenyl ring (bio)isostere, but highly strained caged carbocyclic systems lack π character, which is often critical for mediating key biological interactions. This electronic property restriction associated with cubane has been addressed herein with cyclooctatetraene (COT), using known pharmaceutical and agrochemical compounds as templates. COT either outperformed or matched cubane in multiple cases suggesting that versatile complementarity exists between the two systems for enhanced bioactive molecule discovery.