Preparation of Phosphonic Acid Analogues of Proline and Proline Analogues and Their Biological Evaluation as δ¹‑Pyrroline-5-carboxylate Reductase Inhibitors

Racemic 1-hydroxy-3-butenyl-, 3-chloro-1-hydroxypropyl-, and 3-bromo-1-hydroxypropylphosphonate and the corresponding (<i>S</i>)-enantiomers obtained by lipase-catalyzed resolution of the respective racemic chloroacetates were subjected to functional group manipulations. These comprised ozonolysis, Mitsunobu reactions with hydrazoic acid and <i>N</i>-hydroxyphthalimide, alkylation of hydrazine derivative, removal of phthaloyl group followed by intramolecular substitution, and global deprotection to deliver the racemates and (<i>R</i>)-enantiomers (ee 92–99% by chiral high-performance liquid chromatography) of pyrrolidin-2-yl-, oxazolidin-3-yl-, oxazolidin-5-yl-, pyrazolidin-3-yl-, and 1,2-oxazinan-3-ylphosphonic acids. These phosphonic acids were evaluated as analogues of proline and proline analogues for the ability to inhibit γ-glutamyl kinase, δ¹-pyrroline-5-carboxylate synthetase, and δ¹-pyrroline-5-carboxylate reductase. Only the latter enzyme was inhibited by two of them at concentrations exceeding 1 mM

Bisphosphonic acids as effective inhibitors of <i>Mycobacterium tuberculosis</i> glutamine synthetase

<p>Inhibition of glutamine synthetase (GS) is one of the most promising strategies for the discovery of novel drugs against tuberculosis. Forty-three bisphosphonic and bis-<i>H</i>-phosphinic acids of various scaffolds, bearing aromatic substituents, were screened against recombinant GS from <i>Mycobacterium tuberculosis.</i> Most of the studied compounds exhibited activities in micromolar range, with <i>N</i>-(3,5-dichlorophenyl)-2-aminoethylidenebisphoshonic acid, <i>N</i>-(3,5-difluorophenyl)-2-aminoethylidene-bisphoshonic acid and <i>N</i>-(3,4-dichlorophenyl)-1-hydroxy-1,1-ethanebisphosphonic acid showing the highest potency with kinetic parameters similar to the reference compound – <i>L</i>-methionine-<i>S</i>-sulfoximine. Moreover, these inhibitors were found to be much more effective against pathogen enzyme than against the human ortholog. Thus, with the bone-targeting properties of the bisphosphonate compounds in mind, this activity/selectivity profile makes these compounds attractive agents for the treatment of bone tuberculosis.</p

Tailoring Natural Abenquines To Inhibit the Photosynthetic Electron Transport through Interaction with the D1 Protein in Photosystem II

Abenquines are natural <i>N</i>-acetylaminobenzoquinones bearing amino acid residues, which act as weak inhibitors of the photosynthetic electron transport chain. Aiming to exploit the abenquine scaffold as a model for the synthesis of new herbicides targeting photosynthesis, 14 new analogues were prepared by replacing the amino acid residue with benzylamines and the acetyl with different acyl groups. The synthesis was accomplished in three steps with a 68–95% overall yield from readily available 2,5-dimethoxyaniline, acyl chlorides, and benzyl amines. Key steps include (i) acylation of the aniline, (ii) oxidation, and (iii) oxidative addition of the benzylamino moiety. The compounds were assayed for their activity as Hill inhibitors, under basal, uncoupled, or phosphorylating conditions, or excluding photosystem I. Four analogues showed high effectiveness (IC₅₀ = 0.1–0.4 μM), comparable with the commercial herbicide diuron (IC₅₀ = 0.3 μM). The data suggest that this class of compounds interfere at the reducing side of photosystem II, having protein D1 as the most probable target. Molecular docking studies with the plastoquinone binding site of <i>Spinacia oleracea</i> further strengthened this proposal

Synthetic Analogues of the Natural Compound Cryphonectric Acid Interfere with Photosynthetic Machinery through Two Different Mechanisms

A series of isobenzofuran-1­(3<i>H</i>)-ones (phthalides), analogues of the naturally occurring phytotoxin cryphonectric acid, were designed, synthesized, and fully characterized by NMR, IR, and MS analyses. Their synthesis was achieved via condensation, aromatization, and acetylation reactions. The measurement of the electron transport chain in spinach chloroplasts showed that several derivatives are capable of interfering with the photosynthetic apparatus. Few of them were found to inhibit the basal rate, but a significant inhibition was brought about only at concentrations exceeding 50 μM. Some other analogues acted as uncouplers or energy transfer inhibitors, with a remarkably higher effectiveness. Isobenzofuranone addition to the culture medium inhibited the growth of the cyanobacterium Synechococcus elongatus, with patterns consistent with the effects measured in vitro upon isolated chloroplasts. The most active derivatives, being able to completely suppress algal growth at 20 μM, may represent structures to be exploited for the design of new active ingredients for weed control

Synthesis of Rubrolide Analogues as New Inhibitors of the Photosynthetic Electron Transport Chain

Many natural products have been used as a model for the development of new drugs and agrochemicals. Following this strategy 11 rubrolide analogues, bearing electron-withdrawing and -donating groups at both benzene rings, were prepared starting from commercially available mucobromic acid. The ability of all compounds to inhibit the photosynthetic electron transport chain in the chloroplast was investigated. The rubrolide analogues were effective in interfering with the light-driven ferricyanide reduction by isolated chloroplasts. The IC₅₀ values of the most active derivatives are in fact only 1 order of magnitude higher than those of commercial herbicides sharing the same mode of action, such as Diuron (0.27 μM). QSAR studies indicate that the most efficient compounds are those having higher ability to accept electrons, either by a reduction process or by an electrophilic reaction mechanism. The results obtained suggest that the rubrolide analogues represent promising candidates for the development of new active principles targeting photosynthesis to be used as herbicides

The Fungal Phytotoxin Alternariol 9‑Methyl Ether and Some of Its Synthetic Analogues Inhibit the Photosynthetic Electron Transport Chain

Alternariol and monomethylalternariol are natural phytotoxins produced by some fungal strains, such as <i>Nimbya</i> and <i>Alternaria</i>. These substances confer virulence to phytopathogens, yet no information is available concerning their mode of action. Here we show that in the micromolar range alternariol 9-methyl ether is able to inhibit the electron transport chain (IC₅₀ = 29.1 ± 6.5 μM) in isolated spinach chloroplasts. Since its effectiveness is limited by poor solubility in water, several alternariol analogues were synthesized using different aromatic aldehydes. The synthesized 6<i>H</i>-benzo­[<i>c</i>]­cromen-6-ones, 5<i>H</i>-chromene­[4,3-<i>b</i>]­pyridin-5-one, and 5<i>H</i>-chromene­[4,3-<i>c</i>]­pyridin-5-one also showed inhibitory properties, and three 6<i>H</i>-benzo­[<i>c</i>]­cromen-6-ones were more effective (IC₅₀ = 12.8–22.8 μM) than the lead compound. Their addition to the culture medium of a cyanobacterial model strain was found to inhibit algal growth, with a relative effectiveness that was consistent with their activity <i>in vitro</i>. In contrast, the growth of a nonphotosynthetic plant cell culture was poorly affected. These compounds may represent a novel lead for the development of new active principles targeting photosynthesis