In search of herbistasis: COT-metsulfuron methyl displays rare herbistatic properties.

Weed management is an essential intervention for maintaining food security and protecting biodiversity but is heavily reliant on chemical control measures (, herbicides). Concerningly, only one herbicide has been developed with a new mode of action (MOA) since the 1980s. Therefore, alternative strategies for preventing weed growth need to be explored.

Cage hydrocarbons as linkers in dimeric drug design: Case studies with trimethoprim and tedizolid.

The looming threat of a "post-antibiotic era" has been caused by a rapid rise in antibacterial resistance and subsequent depletion of effective antibiotic agents in the clinic. An efficient strategy to address this shortfall lies in the reengineering of pre-existing and commercially available antibiotic drugs. This is exemplified by dimerization, a design concept in which two pharmacophores are covalently linked to form a new chemical entity.

PhICl is activated by chloride ions.

A study on the potential activating role of pyridine in the electrophilic chlorination of anisole by PhICl2 has led to the discovery that soluble sources of chloride ions activate PhICl2 in the reaction at catalytic loadings, greatly increasing the rate of chlorination. It is further shown that presence of chloride increases the rate of decomposition of PhICl2 into PhI and Cl2. The specific mechanism by which chloride induces electrophilic chlorination and decomposition of PhICl2 remains an open question.

PhI(OTf) Does Not Exist (Yet)*.

PhI(OTf) has been used for the past 30 years as a strong I(III) oxidant for organic and inorganic transformations. It has been reported to be generated in situ from the reactions of either PhI(OAc) or PhI=O with two equivalents of trimethylsilyl trifluoromethanesulfonate (TMS-OTf). In this report it is shown that neither of these reactions generate a solution with spectroscopic data consistent with PhI(OTf) , with supporting theoretical calculations, and thus this compound should not be invoked as the species acting as the oxidant for transformations that have been associated with its use.

Cubane, Bicyclo[1.1.1]pentane and Bicyclo[2.2.2]octane: Impact and Thermal Sensitiveness of Carboxyl-, Hydroxymethyl- and Iodo-substituents.

With the burgeoning interest in cage motifs for bioactive molecule discovery, and the recent disclosure of 1,4-cubane-dicarboxylic acid impact sensitivity, more research into the safety profiles of cage scaffolds is required. Therefore, the impact sensitivity and thermal decomposition behavior of judiciously selected starting materials and synthetic intermediates of cubane, bicyclo[1.1.

Nonclassical Phenyl Bioisosteres as Effective Replacements in a Series of Novel Open-Source Antimalarials.

The replacement of one chemical motif with another that is broadly similar is a common method in medicinal chemistry to modulate the physical and biological properties of a molecule (i.e., bioisosterism).

Rearrangement-Free Hydroxylation of Methylcubanes by a Cytochrome P450: The Case for Dynamical Coupling of C-H Abstraction and Rebound.

The highly strained cubylmethyl radical undergoes one of the fastest radical rearrangements known (reported = 2.9 × 10 s at 25 °C) through scission of two bonds of the cube. The rearrangement has previously been used as a mechanistic probe to detect radical-based pathways in enzyme-catalyzed C-H oxidations.

Basimarols A, B, and C, Highly Oxygenated Pimarane Diterpenoids from .

The highly oxygenated pimarane diterpenoids basimarols A, B, and C (-) were isolated from the plant species , which was collected within the Australian arid zone. Structure elucidation was performed using a suite of spectroscopic techniques, including X-ray crystallography. Anticancer and anti-DENV activity of - was explored, but only limited activity was observed.

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).

Determining the necessity of phenyl ring π-character in warfarin.

Despite the difficulty in administering a safe dose regimen and reports of emerging resistance, warfarin (1) remains the most widely-used oral anticoagulant for the prevention and treatment of thrombosis in humans globally. Systematic substitution of the warfarin phenyl ring with either 1,3,5,7-cyclooctatetraene (COT) (2), cubane (3), cyclohexane (4) or cyclooctane (5) and subsequent evaluation against the target enzyme, vitamin K epoxide reductase (VKOR), facilitated interrogation of both steric and electronic properties of the phenyl pharmacophore. The tolerance of VKOR to further functional group modification (carboxylate 14, PTAD adduct 15) was also investigated.

Stachyonic Acid: A Dengue Virus Inhibitor from Basilicum polystachyon.

Stachyonic acid A, arising from the first in-depth phytochemical investigation of the herb Basilicum polystachyon, was found to display potent inhibitory activity against dengue virus, with limited cytotoxicity. Andrographolide, a known dengue virus inhibitor and closely related labdane-type diterpene, is structurally more complex but displayed poor antiviral activity in the PRNT assay, and increased cytotoxicity in comparison. Furthermore, a Diels-Alder reaction with PTAD identified the active pharmacophore of stachyonic acid to be the conjugated diene.

Cyclooctatetraenes through Valence Isomerization of Cubanes: Scope and Limitations.

The scope and limitations of Eaton's rhodium(I)-catalyzed valence isomerization of cubane to cyclooctatetraene (COT) were investigated in the context of functional group tolerability, multiple substitution modes and the ability of cubane-alcohols to undergo one-pot tandem Ley-Griffith Wittig reactions in the absence of a transition metal catalyst.

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.

Enantioselective synthesis of (R)-2-cubylglycine including unprecedented rhodium mediated C-H insertion of cubane.

The first enantioselective synthesis of (R)-2-cubylglycine, an analogue of (R)-2-phenylglycine in which the phenyl ring has been replaced by cubane, is disclosed. The key step was a telescoped Strecker reaction using (S)-2-amino-2-phenylethanol as a chiral auxiliary. Exploration of an alternative synthetic approach resulted in unprecedented cubane C-H insertion.