Mesoionic Derivatives Research Articles

Design, Synthesis, and Biological Evaluation of Pyrido [1,2-α] Pyrimidinone Mesoionic Derivatives Bearing Propenylbenzene as the Vector Control Insecticide.

A series of novel pyrido [1,2-α] pyrimidinone mesoionic derivatives bearing a propenylbenzene group at the 1-position were synthesized on the basis of the structure of mesoionic insecticides triflumezopyrim and dicloromezotiaz via a rationally conceived pharmacophore model and evaluated for their insecticidal activities against three insect vectors. The bioassay results showed that some compounds exerted remarkable insecticidal activities against M. domestica, Ae. albopictus, and B. germanica. Particularly, compound 26l displayed outstanding insecticidal activity against Ae. Albopictus, with an LC50 value of 0.45 μg/mL, far superior to that of imidacloprid (LC50 = 1.82 μg/mL) and equivalent to that of triflumezopyrim (0.35 μg/mL). Meanwhile, compound 34l presented a broad insecticidal spectrum, with LC50 values of 1.51 μg/g sugar, 0.52 μg/mL and 0.14 μg/adult, which were about 2.88, 3.50, and 1.50 times better than that of imidacloprid (LC50 = 4.35 μg/g sugar, 1.82 μg/mL and 0.21 μg/adult against M. domestica, Ae. albopictus, and B. germanica, respectively) and equivalent to that of triflumezopyrim against M. domestica (1.13 μg/g sugar) and Ae. albopictus (0.35 μg/mL) but lower than the potency against B. germanica (0.06 μg/g sugar). The molecular docking study by energy minimizations revealed that introducing propenylbenzene at the 1-position of compounds 26l and 34l could embed into the binding pocket of nicotinic acetylcholine receptors and form pi-alkyl interaction with LEU306. These results demonstrated that compounds 26l and 34l could be promising candidates for vector control insecticides, which deserved further investigation.

Synthesis, insecticidal activity, and mode of action of novel imidazopyridine mesoionic derivatives containing an amido group

In our previous work, we applied a new synthetic strategy to design and synthesize a series of imidazopyridine mesoionic derivatives with an ester group. The newly synthesized compounds had excellent insecticidal activity against aphids; however, insecticidal activity against planthoppers was less than satisfactory. In the present study, we designed and synthesized a series of novel imidazopyridine mesoionic compounds, containing an amido group, and these compounds were found to have improved insecticidal activity against planthoppers. The bioassay results demonstrated that most of the target compounds had moderate-to-good insecticidal activity against Sogatella furcifera, and some exhibited good-to-excellent insecticidal activity against Aphis craccivora. Among them, compound C6 had the highest insecticidal activity against S.furcifera and A.craccivora, with LC50 values of 10.5 and 2.09 μg mL-1 , respectively. Proteomic results suggested that the differentially expressed proteins mainly were enriched in the nervous system-related pathways after compound C6 treatment. Enzymatic assay results showed that compound C6 and triflumezopyrim had a certain inhibitory effect on acetylcholinesterase. Molecular docking and real-time quantitative PCR results indicated that compound C6 not only may act on the nicotinic acetylcholine receptor, but also may interact with the α4 and β1 subunits of this receptor. The results reported here contribute to the development of new mesoionic insecticides and further our understanding of the mode-of-action of imidazopyridine mesoionic derivatives. © 2022 Society of Chemical Industry.

Pyrido [1,2-a] Pyrimidinone Mesoionic Compounds Containing Vanillin Moiety: Design, Synthesis, Antibacterial Activity, and Mechanism.

Xanthomonas oryzae pv. oryzicola (Xoo) is a plant pathogen responsible for rice bacterial blight disease that remains challenging for prevention and cure. To discover innovative and extremely potent antibacterial agents, vanillin moiety was introduced to develop a series of novel mesoionic derivatives. Compound 15 demonstrated excellent in vitro antibacterial activity against Xoo, with a 50% effective concentration value (EC50) of 27.5 μg/mL, which was superior to that of the positive control agent thiodiazole copper (97.1 μg/mL) and comparable to that of compound "A11" (17.4 μg/mL). The greenhouse pot experiment also revealed that compound 15 had 38.5% curative and 36.8% protective efficacy against rice bacterial leaf blight in vivo at 100 μg/mL, which was higher than those of thiodiazole copper (31.2 and 32.6%, respectively) and compound "A11" (29.6 and 33.2%, respectively). Compound 15 enhanced the activities of related defense enzymes, increased chlorophyll content, and promoted the resistance of rice to bacterial infection by modulating the photosynthetic pathway. This study provides a basis for the subsequent structural modification and mechanism research of mesoionic derivatives.

Discovery of Mesoionic Derivatives Containing a Dithioacetal Skeleton as Novel Potential Antibacterial Agents and Mechanism Research.

In this study, the design and synthesis of novel pyrido[1,2-a]pyrimidinone mesoionic derivatives incorporating dithioacetal structures were carried out. The three-dimensional quantitative structure-activity relationship (3D-QSAR) model was built according to the EC50 values and directed the synthesis of compound A32. The biological activity test against Xanthomonas oryzae pv. oryzae (Xoo) and Xanthomonas oryzae pv. oryzicola (Xoc) indicated that compound A32 showed good antibacterial activity with EC50 values of 10.9 and 17.5 mg/L, which were lower than the EC50 values of bismerthiazol (29.3 and 39.8 mg/L) and thiodiazole copper (64.8 and 78.1 mg/L). Furthermore, the in vivo antibacterial activity against bacterial leaf blight (BLB) and bacterial leaf streak (BLS) revealed that the protective activity of compound A32 was 43.9 and 41.7%, respectively, which was better than the protective activity of thiodiazole copper (40.6 and 35.0%). In addition, the protective activity against bacterial leaf blight of compound A32 was associated with the increasing rice defensive enzyme activity and the upregulation of proteins involved in oxidative phosphorylation. Moreover, compound A32 could upregulate the expression of complex I (nicotinamide adenine dinucleotide hydrogen (NADH) dehydrogenase) in the oxidative phosphorylation pathway, which was verified by complex I activity evaluation.

New Synthetic Method and Insecticidal Activities of Novel Imidazopyridine Mesoionic Derivatives Containing an Ester Group.

To develop novel insecticides with high efficiency, a new mode of action, and safety to nontarget organisms and the environment, a series of imidazopyridine mesoionic compounds containing an ester group have been designed and synthesized via a new synthetic method discovered by our group. The bioactivity results showed that most of the target compounds exhibited significant insecticidal activities against Aphis craccivora, and some of them showed moderate insecticidal activities against Sogatella furcifera. Among them, compounds C2, C4-C11, and D3 showed excellent insecticidal activities against A. craccivora (LC50 values were lower than 4.5 μg/mL), which were superior to those of pymetrozine (LC50 = 6.19 μg/mL) and triflumezopyrim (LC50 = 4.68 μg/mL). Remarkably, the insecticidal activity of compound C9 was 5.9-fold greater than that of triflumezopyrim with an LC50 value of 0.8 μg/mL. Proteomics and molecular docking results indicated that compound C9 may affect the nervous system of A. craccivora and act on nicotinic acetylcholine receptors like triflumezopyrim.

Discovery of Novel Benzo[4,5]thiazolo(oxazolo)[3,2-a]pyrimidinone Mesoionic Derivatives as Potential Antibacterial Agents and Mechanism Research.

A series of benzo[4,5]thiazole(oxazole)[3,2-a]pyrimidine mesoionic compounds were designed and synthesized. Antibacterial activity tests revealed that compound A23 showed good in vitro activities against Xanthomonas oryzae pv. Oryzicola (Xoc) and Xanthomonas oryzae pv. oryzae (Xoo), with half-maximal effective concentration (EC50) values of 47.6 and 36.8 μM, respectively, which were better than positive control agents thiodiazole copper (281 and 259 μM) and bismerthiazol (245 and 220 μM). The protective activities of compound A23 anti-Xoc and anti-Xoo were 39.7% and 49.2%, respectively, which were better than those of bismerthiazol (31.5% and 40.7%). Compound A23 improved defensive enzyme activities in rice. In addition, compound A23 could upregulate the expression of succinate dehydrogenase (SDH) in the oxidative phosphorylation (OXPHOS) pathway through proteomics analysis, which was consistent with the result of the SDH activity test. Thus, compound A23 is a novel potential antibacterial agent that can be further developed.

The toxicity of 1,3,4-thiadiazolium mesoionic derivatives on hepatocarcinoma cells (HepG2) is associated with mitochondrial dysfunction

Mesoionic compounds, 4-phenyl-5-(4-X-cinnamoyl)-1,3,4-thiadiazolium-2-phenylamine chloride derivatives (MI-J: X = OH; MI-D: X = NO2), possess significant antitumor and cytotoxic effects on several cancer cells. In this work, we evaluated the cytotoxicity of MI-J and MI-D on human hepatocellular carcinoma (HepG2 cells) grown in either high glucose (HG) or galactose medium (GAL) to clarify whether the effects of mesoionics on mitochondrial bioenergetics are associated with their cytotoxicity in these cells. MI-J and MI-D (5–50 μM) decreased the viability of HepG2 cells in a dose- and time-dependent manner, as assessed by MTT, LDH release and dye with crystal violet assays. Both compounds at lower (5 μM) and intermediate (25 μM) concentrations were more toxic to cells grown in GAL medium. MI-J inhibited the basal state of respiration in HepG2 cells cultured in HG and GAL media; however, in GAL medium, this effect occurred at the lowest concentration (5 μM). A leak-state stimulus was observed only after incubation with MI-J (5 μM) for GAL medium. MI-D stimulated and inhibited the leak state in cells grown in HG medium at concentrations of 5 μM and 25 μM, respectively. In cells cultured in GAL medium, respiration was strongly inhibited by MI-D at the highest concentration (25 μM). In contrast, at 5 μM, the mesoionic inhibited the basal and uncoupled states at 30% and 50%, respectively. The inhibition of the basal state by MI-J and MI-D was consistent with the increase in lactate levels in both media, which was higher for the GAL medium. Both mesoionics slightly decreased pyruvate levels only in cells cultured in GAL medium. Additionally, MI-J (25 μM) reduced the ATP amount in cells cultured in both media, while MI-D (25 μM) promoted a reduction only in cells grown in GAL medium. Our results show that MI-J and MI-D depress mitochondrial respiration and consequently change metabolism and reduce ATP levels, effects associated with their toxicity in hepatocarcinoma cells.

Novel trifluoromethyl sydnone derivatives: Design, synthesis and fungicidal activity

Crop pathogens reduce the yield and quality of agricultural production. The development of new fungicides will help to sustain this protection and overcome fungicide resistance. Sydnone is a kind of mesoionic, which has a wide range of biological activities. The application of sydnones in agriculture is less, and the study of these compounds will lead to the discovery of new active compounds. In this study, we designed and synthesized a series of noval sydnone mesoionic derivatives by active substructure splicing. All compounds were characterized using 1H and 13C NMR spectroscopy. Among them, trifluoromethyl compound D17 showed good bioactivity against Pseudoperonospora cubensis (EC50 = 49 mg L−1) in vivo, the activity was similar to that of the control Kresoxim-methyl (EC50 = 44 mg L−1). However, the target of these compounds should not only be tyrosinase, and the mode of action needs to be further studied. In addition, the structure–activity relationship indicated that the trifluoromethyl group was more beneficial for antifungal activity. This is the first report that fluorine-containing N(3)-benzyl sydnone compounds have good fungicidal activity. These results will provide a basis for the development of sydnone mesoionic as new lead fungicidal agents.

Air‐Stable Oxyallyl Patterns and a Switchable N‐Heterocyclic Carbene

AbstractOxyallyl derivatives are typically elusive compounds. Even recently reported “stabilized” 1,3‐diaminooxyallyl species are still highly reactive and have short lifetimes at room temperature. Herein, we report the synthesis and preliminary study of mesoionic pyrimidine derivatives that feature 1,3‐bis(dimethylamino)oxyallyl patterns with an unprecedented level of stabilization. The latter are not only insensitive towards air and moisture, but they are also compatible with the formation of an ancillary stable N‐heterocyclic carbene moiety. As the oxyallyl pattern is proton‐responsive, it allows the reversible switching of the electronic properties of the carbene, as a ligand.

Air-Stable Oxyallyl Patterns and a Switchable N-Heterocyclic Carbene.

Oxyallyl derivatives are typically elusive compounds. Even recently reported "stabilized" 1,3-diaminooxyallyl species are still highly reactive and have short lifetimes at room temperature. Herein, we report the synthesis and preliminary study of mesoionic pyrimidine derivatives that feature 1,3-bis(dimethylamino)oxyallyl patterns with an unprecedented level of stabilization. The latter are not only insensitive towards air and moisture, but they are also compatible with the formation of an ancillary stable N-heterocyclic carbene moiety. As the oxyallyl pattern is proton-responsive, it allows the reversible switching of the electronic properties of the carbene, as a ligand.

Novel piperonal 1,3,4-thiadiazolium-2-phenylamines mesoionic derivatives: Synthesis, tyrosinase inhibition evaluation and HSA binding study

A novel series of piperonal mesoionic derivatives (PMI 1–6) was synthesized. Tyrosinase inhibition in the presence of PMI-1, −2, −3, −4, −5 and −6 as well as human serum albumin (HSA) binding studies with PMI-5 and PMI-6 were done by spectroscopic and theoretical methods. The mesoionic compound PMI-5 is the most promising tyrosinase inhibitor with a noncompetitive inhibitory mechanism and an IC50=124μmolL−1. In accordance with the kinetic profile, molecular docking results show that PMI-5 is able to interact favorably with the tyrosinase active site containing the substrate molecule, L-DOPA, interacting with Val-247, Phe-263 and Val-282 residues. The spectroscopic results for the interaction HSA:PMI-5 and HSA:PMI-6 indicated that these mesoionic compounds can associate with HSA in the ground state and energy transfer can occur with high probability. The binding was moderate, spontaneous and can perturb significantly the secondary structure of the albumin. The molecular docking results suggest that PMI-5 and PMI-6 are able to be accommodated inside the Sudlow's site I in HSA, interacting with hydrophobic and hydrophilic amino acid residues.

ChemInform Abstract: Synthesis of Mesoionic Isoquinolines by Rhodium(III)‐Catalyzed C—H Activation.

Hydroxyl-substituted benzaldimines underwent a Rh(III) -catalyzed C-H activation and annulation with alkynes to provide novel mesoionic isoquinoline derivatives in moderate to excellent yields using oxygen as an internal anion source. This simple and efficient approach has a broad substrate scope.

Synthesis of Mesoionic Isoquinolines by Rhodium(III)-Catalyzed C-H Activation.

Hydroxyl-substituted benzaldimines underwent a Rh(III) -catalyzed C-H activation and annulation with alkynes to provide novel mesoionic isoquinoline derivatives in moderate to excellent yields using oxygen as an internal anion source. This simple and efficient approach has a broad substrate scope.

Efficient Approach to Mesoionic Triazolo[5,1-a]isoquinolium through Rhodium-Catalyzed Annulation of Triazoles and Internal Alkynes.

Rhodium-catalyzed annulation reactions between triazoles and internal alkynes, leading to various mesoionic isoquinoliums, are described. The reaction involves sequential triazole-directed C-H activation and C-C, C-N, and C-O bond formation processes in a one-pot manner. The starting materials and catalysts are easily available. The reaction offers a facile and practical approach to mesoionic isoquinolium derivatives.

In vitro evaluation of 4-phenyl-5-(4′-X-phenyl)-1,3,4-thiadiazolium-2-phenylaminide chlorides and 3[N-4′-X-phenyl]-1,2,3-oxadiazolium-5-olate derivatives on nitric oxide synthase and arginase activities of Leishmania amazonensis

Leishmaniasis is a spectrum of infectious diseases caused by Leishmania protozoan parasites. The purpose of this study was to perform, in vitro, a comparative analysis of the activity amastigotes. Results showed excellent efficacy of all compounds against axenic amastigotes, compared to pentamidine isethionate, the reference drug used. The cytotoxic effect of these mesoionic compounds of six mesoionic compounds (three 1,3,4-thiadiazolium-2-aminide and three 1,2,3-oxadiazolium-5-olate class compounds) was evaluated in mouse peritoneal macrophages using MTT assay, low toxicity (∼10%) for these mammalian cells being observed. In an attempt to define a potential drug target, the activities of nitric oxide synthase (NOS) and arginase of the parasites treated with the mesoionic derivatives were evaluated. NOS was purified from a cell-free extract of infective promastigotes and axenic amastigotes and all derivatives tested were able to inhibit the enzyme as monitored by the decrease of NADPH consumption. Arginase activity from both stages of the parasite was measured using urea production and none of the compounds inhibited the enzyme activity of axenic amastigotes. However, the compounds without substituents (MI-H and SID-H) were able to inhibit arginase activity of these parasites.

Interaction of 1,3,4-thiadiazolium mesoionic derivatives with mitochondrial membrane and scavenging activity: Involvement of their effects on mitochondrial energy-linked functions

The aim of this work was to assess the significance of the interaction of the 1,3,4-thiadiazolium derivatives MI-J, MI-4F and MI-2,4diF with mitochondrial membrane and their effects on energy-linked functions. Mitochondrial swelling in the absence of substrate was inhibited by all derivatives; however, the fluorine derivatives were most effective. MI-4F decreased swelling by ∼32% even at the lowest concentration (65nmolmg−1 protein), reaching ∼67% at the concentration of 130nmolmg−1 protein. Swelling of mitochondria in the presence of oxidizable substrates was also strongly decreased by all derivatives. This effect was more pronounced when using glutamate plus malate, and also fluorine derivatives, which promoted complete inhibition at all concentrations (6.5–130nmolmg−1 protein). Swelling occurred when succinate was the substrate in the presence of MI-J (6.5–65nmolmg−1 protein); however, the shrinkage rate was strongly decreased. MI-4F and MI-2,4diF also inhibited swelling, with total inhibition occurring at a concentration of 65nmolmg−1 protein. Lipid peroxidation induced by Fe3+–ADP/2-oxoglutarate in isolated mitochondria was inhibited time- and dose-dependently by the derivatives, reaching complete inhibition at the highest concentration (80nmolmg−1 protein). However, when lipid peroxidation was initiated by peroxyl radicals generated from AAPH, the inhibition was less intense, reaching ∼50%, ∼40% and ∼58% with MI-J, MI-4F and MI-2,4diF (80nmolmg−1 protein), respectively. The mesoionic compounds also showed superoxide radical scavenging ability of ∼22%, ∼32% and ∼40% (80nmolmg−1 protein), respectively. Fluorescence polarization experiments showed that the derivatives are able to enter the bilayer, decreasing its fluidity in the hydrophobic DMPC membrane region and ordering the fluid phase. Our results suggest that MI-J, MI-4F and MI-2,4diF interact significantly, albeit in different modes, with mitochondrial membrane, and that fluorine derivatives seem to alter the membrane's properties more markedly.

Comparative study of the effects of 1,3,4-thiadiazolium mesoionic derivatives on energy-linked functions of rat liver mitochondria

The main goal of this work was to investigate the relationship between the effects of three new 1,3,4-thiadiazolium mesoionic derivatives on mitochondrial bioenergetics and their previously described chemical structure and antimelanoma activity. The 4-phenyl-5-(2′-Y, 4′-X or 4′-X-cinnamoyl)-1,3,4-thiadiazolium-2-phenylamine chlorides differed from each other only in the cinnamoyl ring substituent: MI-J, X = OH; MI-F, X = F; MI-2,4diF X = Y = F. The state 3 respiratory rate was strongly decreased by all derivatives, reaching total inhibition of MI-4F and MI-2,4diF (130 nmol mg −1 protein), when glutamate plus malate were used as substrate. State 3 inhibition was less accentuated with succinate as substrate. Analyses of segments of the respiratory chain indicated complexes I and IV as sites inhibited by the derivatives. State 4 respiration was strongly stimulated by the three derivatives, and was characterized as an uncoupling effect, which was more intense for MI-4F. This stimulus was so pronounced that the values of RCC and ADP/O ratio were only calculated for the lowest concentration (6.5 nmol mg −1 protein). In intact mitochondria, the ATPase activity was increased dramatically by ∼120%, ∼207% and ∼261% for MI-J, MI-4F and MI-2,4diF (32.5 nmol mg −1 protein), respectively. In conclusion, the presence of fluorine substituent in the cinnamoyl ring intensifies the effect of mesoionic compounds on mitochondrial functions and, in this context, hydrophobicity is more important than the electronic effect, which was correlated to antimelanoma activity described previously for these compounds.

Antileishmanial Activity of 1,3,4-Thiadiazolium-2-Aminide in Mice Infected withLeishmania amazonensis

The efficacy of two mesoionic derivatives (MI-H-H and MI-4-OCH(3)) was evaluated in CBA/J mice infected with Leishmania amazonensis. Treatment with these compounds demonstrated that the MI-4-OCH(3) derivative and the reference drug meglumine antimoniate (Glucantime) presented significant activity relative to an untreated control. No apparent hepatic or renal toxicity due to these mesoionic compounds was found.

Effect of mesoionic 4-phenyl-5-(cinnamoyl)-1,3,4-thiadiazolium-2-phenylamine chloride derivative salts on the activities of the nitric oxide synthase and arginase of Leishmania amazonensis

l-arginine is involved in the production of both nitric oxide (NO), mediated by nitric oxide synthase (NOS) and l-ornithine, by arginase activity. It is generally accepted that NO regulation occurs mainly at the transcriptional level of NOS. In a previous work we purported that there is evidence that Leishmania sp. can produce NO from l-arginine. An arginase activity in its gene sequence has also been reported in Leishmania parasites. In a search for intracellular targets as potential antileishmanicidal agents, such as the l-arginine metabolism, we used 1,3,4-thiadiazolium mesoionic compounds, that have been demonstrated to be cytotoxic to the Leishmania amazonensis, when compared to Pentamidine isethionate as a reference drug. Parasites were assayed in absence/presence of 4′- and 3′- methoxy mesoionic derivatives in order to verify the effect on NO production and arginase activity in L. amazonensis. The results indicated that the drugs reduce from 70 to 90% of the NO production by the parasite and act on a soluble nitric oxide synthase purified from L. amazonensis promastigotes and axenic amastigotes.

Electrochemical behavior of mesoionic sydnone derivatives at wax-impregnated carbon paste electrode

The-N=N-moiety in the mesoionic 3-phenyl sydnone and its derivatives like tolyl sydnones and anisyl sydnones undergo two-electron irreversible electrochemical reduction in Britton-Robinson (BR) buffer at wax-impregnated carbon paste electrodes. Infrared, nuclear magnetic resonance, and mass-spectral data, used to characterize the reduced product, confirm the proposed mechanism. The pasting liquid at the surface of the electrode is found to decrease the electron-transfer rate and cause a higher overpotential compared to homogeneous electrodes. The influence of variation of pH on the peak current and peak potentials is studied in the acidic range. The cathodic peak shifts to more negative potentials with increase in pH, indicating the involvement of proton in the reduction process. This could be a new method of preparation of 2,4-dihydro-3-substituted 1,2,3-oxadiazole-5-one. The substituent effect and the effect of variation of scan rate, concentration, and temperature on peak currents and peak potentials is discussed. The cathodic shift in various organic co-solvents (methanol, acetonitrile, DMF, DMSO) using BRB as the supporting electrolyte is examined.