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.

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

The unusual and sterically constrained amino acid, -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.

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.

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

-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.

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.

Comprehensive Computational Investigation of the Barton-Kellogg Reaction for Both Alkyl and Aryl Systems.

The course of the Barton-Kellogg (BK) reaction for alkyl- and aryl-substituted substrates has been investigated at the DLPNO-CCSD(T)/def2-TZVPP//ωB97X-D/def2-TZVPP level of theory, with results compared to available experimental kinetic data. Through comparison with the unsubstituted parent system, the preference for the formation of 1,3,4-dihydrothiadiazole over the isomeric 1,2,3-dihydrothiadiazole was observed to result from reduced steric repulsion in the relevant transition-state structure. Nitrogen extrusion [retro-(3 + 2)-cycloaddition] from the intermediate dihydrothiadiazole was found to be the rate-determining step.

GlycoTorch Vina: Docking Designed and Tested for Glycosaminoglycans.

Glycosaminoglycans (GAGs) are a family of anionic carbohydrates that play an essential role in the physiology and pathology of all eukaryotic life forms. Experimental determination of GAG-protein complexes is challenging due to their difficult isolation from biological sources, natural heterogeneity, and conformational flexibility-including possible ring puckering of sulfated iduronic acid from C to S conformation. To overcome these challenges, we present GlycoTorch Vina (GTV), a molecular docking tool based on the carbohydrate docking program VinaCarb (VC).

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.

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).

Pathway Bifurcation in the (4 + 3)/(5 + 2)-Cycloaddition of Butadiene and Oxidopyrylium Ylides: The Significance of Molecular Orbital Isosymmetry.

By drawing analogies from the dimerization of cyclopentadiene, a novel reaction pathway bifurcation is uncovered in the cycloaddition of oxidopyrylium ylides and butadiene. Analysis of the potential energy surface (at the M06-2X/6-311+G(d,p) level of theory) in combination with Born-Oppenheimer molecular dynamics simulations (M06-2X/6-31+G(d)) demonstrate that both the (4 + 3)- and (5 + 2)-cycloaddition products are accessed from the same transition state. Key indicators of a pathway bifurcation (asynchronous bond formation, and a second transition state for the interconversion of the products) are also observed.

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.

Synthesis of the seco-Limonoid BCD Ring System Identifies a Hsp90 Chaperon Machinery (p23) Inhibitor.

D-Ring-seco-limonoids (tetranortriterpenoids), such as gedunin and xylogranin B display anti-cancer activity, acting via inhibition of Hsp90 and/or associated chaperon machinery (e.g., p23).

Computational evidence for a reaction pathway bifurcation in Sasaki-type (4 + 3)-cycloadditions.

The current report seeks to validate the existence of a post-transition state bifurcation in the Lewis acid-catalysed (4 + 3)-cycloaddition of butadiene and α-methoxy acrolein. Cycloaddition transition state (TS) structures are shown by intrinsic reaction coordinate (IRC) and potential energy surface (PES) scan calculations to connect directly to both (4 + 3)- and (4 + 2)-products. A second TS, a 1,2-sigmatropic shift which interconverts the products, was also located.

Claisen rearrangements of benzyl vinyl ethers: theoretical investigation of mechanism, substituent effects, and regioselectivity.

Recently we reported the aromatic Claisen rearrangements of benzyl ketene acetals, which form one of the few examples of aromatic Claisen rearrangements involving benzyl vinyl ethers (as opposed to allyl aryl ethers, which are the usual substrates for aromatic Claisen rearrangements). Theoretical calculations predict that these rearrangements proceed via a concerted [3,3]-sigmatropic transition state, which is similar in geometry to the TS for the Claisen rearrangement of an allyl aryl ether but has a 4 kcal mol higher barrier. The effects of donor (OMe) and acceptor (CN) substituents on the kinetics of the [3,3]-rearrangement mirror those reported for allyl vinyl ethers: the largest substituent effects are seen for 1-OMe, 2-OMe, 2-CN, and 4-CN substituents, which lower the barrier by 5-9 kcal mol.