Synthesis, carbonic anhydrase inhibition studies and modelling investigations of phthalimide-hydantoin hybrids.

A novel series of hydantoins incorporating phthalimides has been synthesised by condensation of activated phthalimides with 1-aminohydantoin and investigated for their inhibitory activity against a panel of human (h) carbonic anhydrase (CA, EC 4.2.1.1): the cytosolic isoforms hCA I, hCA II, and hCA VII, secreted isoform hCA VI, and the transmembrane hCA IX, by a stopped-flow CO2 hydrase assay. Although all newly developed compounds were totally inactive on hCA I and mainly ineffective towards hCA II, they generally exhibited moderate repressing effects on hCA VI, VII, and IX with KIs values in the submicromolar to micromolar ranges. The salts 3a and 3b, followed by derivative 5, displayed the best inhibitory activity of all the evaluated compounds and their binding mode was proposed in silico. These compounds can also be considered interesting starting points for the development of novel pharmacophores for this class of enzyme inhibitors.

Novel triterpenoid pyrones, phthalimides and phthalates are selectively cytotoxic in CCRF-CEM cancer cells - Synthesis, potency, and mitochondrial mechanism of action.

A series of triterpenoid pyrones was synthesized and subsequently modified to introduce phthalimide or phthalate moieties into the triterpenoid skeleton. These compounds underwent in vitro cytotoxicity screening, revealing that a subset of six compounds exhibited potent activity, with IC50 values in the low micromolar range. Further biological evaluations, including Annexin V and propidium iodide staining experiment revealed, that all compounds induce selective apoptosis in cancer cells. Measurements of mitochondrial potential, cell cycle analysis, and the expression of pro- and anti-apoptotic proteins confirmed, that apoptosis was mediated via the mitochondrial pathway. These findings were further supported by cell cycle modulation and DNA/RNA synthesis studies, which indicated a significant increase in cell accumulation in the G0/G1 phase and a marked reduction in S-phase cells, alongside a substantial inhibition of DNA synthesis. The activation of caspase-3 and the cleavage of PARP, coupled with a decrease in the expression of Bcl-2 and Bcl-XL proteins, underscored the induction of apoptosis through the mitochondrial pathway. Given their high activity and pronounced effect on mitochondria function, trifluoromethyl pyrones 1f and 2f, and dihydrophthalimide 2h have been selected for further development.

Phenotypic screening reveals a highly selective phthalimide-based compound with antileishmanial activity.

Pharmacophores such as hydroxyethylamine (HEA) and phthalimide (PHT) have been identified as potential synthons for the development of compounds against various parasitic infections. In order to further advance our progress, we conducted an experiment utilising a collection of PHT and HEA derivatives through phenotypic screening against a diverse set of protist parasites. This approach led to the identification of a number of compounds that exhibited significant effects on the survival of Entamoeba histolytica, Trypanosoma brucei, and multiple life-cycle stages of Leishmania spp. The Leishmania hits were pursued due to the pressing necessity to expand our repertoire of reliable, cost-effective, and efficient medications for the treatment of leishmaniases. Antileishmanials must possess the essential capability to efficiently penetrate the host cells and their compartments in the disease context, to effectively eliminate the intracellular parasite. Hence, we performed a study to assess the effectiveness of eradicating L. infantum intracellular amastigotes in a model of macrophage infection. Among eleven L. infantum growth inhibitors with low-micromolar potency, PHT-39, which carries a trifluoromethyl substitution, demonstrated the highest efficacy in the intramacrophage assay, with an EC50 of 1.2 +/- 3.2 µM. Cytotoxicity testing of PHT-39 in HepG2 cells indicated a promising selectivity of over 90-fold. A chemogenomic profiling approach was conducted using an orthology-based method to elucidate the mode of action of PHT-39. This genome-wide RNA interference library of T. brucei identified sensitivity determinants for PHT-39, which included a P-type ATPase that is crucial for the uptake of miltefosine and amphotericin, strongly indicating a shared route for cellular entry. Notwithstanding the favourable properties and demonstrated efficacy in the Plasmodium berghei infection model, PHT-39 was unable to eradicate L. major infection in a murine infection model of cutaneous leishmaniasis. Currently, PHT-39 is undergoing derivatization to optimize its pharmacological characteristics.

Phthalimide-tethered isatins as novel poly(ADP-ribose) polymerase inhibitors: Design, synthesis, biological evaluations, and molecular modeling investigations.

Humanity is currently facing various diseases with significant mortality rates, particularly those associated with malignancies. Numerous enzymes and proteins have been identified as highly promising targets for the treatment of cancer. The poly(ADP-ribose) polymerases (PARPs) family comprises 17 members which are essential in DNA damage repair, allowing the survival of cancer cells. Unlike other PARP family members, PARP-1 and, to a lesser extent, PARP-2 show more than 90% activity in response to DNA damage. PARP-1 levels were shown to be elevated in various tumor cells, including breast, lung, ovarian, and prostate cancer and melanomas. Accordingly, novel series of phthalimide-tethered isatins (6a-n, 10a-e, and 11a-e) were synthesized as potential PARP-1 inhibitors endowed with anticancer activity. All the synthesized molecules were assessed against PARP-1, where compounds 6f and 10d showed nanomolar activities with IC50 = 15.56 ± 2.85 and 13.65 ± 1.42 nM, respectively. Also, the assessment of the antiproliferative effects of the synthesized isatins was conducted on four cancer cell lines: leukemia (K-562), liver (HepG2), and breast (MCF-7 and HCC1937) cancers. Superiorly, compounds 6f and 10d demonstrated submicromolar IC50 values against breast cancer MCF-7 (IC50 = 0.92 ± 0.18 and 0.67 ± 0.12 µM, respectively) and HCC1937 (IC50 = 0.88 ± 0.52 and 0.53 ± 0.11 µM, respectively) cell lines. In addition, compounds 6f and 10d induced arrest in the G2/M phase of the cell cycle as compared to untreated cells. Finally, in silico studies, including docking and molecular dynamic simulations, were performed to justify the biological results.

Click chemistry inspired facile one-pot synthesis of mannosyl triazoles and their hemagglutination inhibitory properties: The effect of alkyl chain spacer length between the triazole and phthalimide moieties in the aglycone backbone.

An efficient one-pot synthesis of a new series of mannosyl triazoles has been achieved through CuAAC reaction where the alkyl chain spacer between the phthalimide moiety and the triazole ring in the aglycone backbone is varied from one methylene to six methylene units. The target compounds were evaluated in terms of their inhibitory potency against FimH using hemagglutination inhibition (HAI) assay. It was found that the length of four methylene units was the optimum for the fitting/binding of the compound to FimH as exemplified by compound 11 (HAI = 1.9 µM), which was approximately 200 times more potent than the reference ligand 1(HAI = 385 µM). The successful implementation of one-pot protocol with building blocks 1-7 and the architecture of ligand 11 will be the subject of our future work for developing more potent FimH inhibitors.

Exploration of the novel phthalimide-hydroxypyridinone derivatives as multifunctional drug candidates against Alzheimer's disease.

A novel series of phthalimide-hydroxypyridinone derivatives were rationally designed and evaluated as potential anti-Alzheimer's disease (AD) agents. Bioactivity tests showed that all compounds displayed great iron ions-chelating activity (pFe3+ = 17.07-19.52), in addition to potent inhibition of human monoamine oxidase B (hMAO-B). Compound 11n emerged as the most effective anti-AD lead compound with a pFe3+ value of 18.51, along with selective hMAO-B inhibitory activity (IC50 = 0.79 ± 0.05 µM, SI > 25.3). The results of cytotoxicity assays demonstrated that 11n showed extremely weak toxicity in PC12 cell line at 50 µM. Additionally, compound 11n displayed a cytoprotective effect against H2O2-induced oxidative damage. Moreover, compound 11n exhibited ideal blood-brain barrier (BBB) permeability in the parallel artificial membrane permeation assay (PAMPA), and significantly improved scopolamine-induced cognitive and memory impairment in mice behavioral experiments. In conclusion, these favorable experimental results suggested compound 11n deserved further investigation as an anti-AD lead compound.

Synthesis and cytotoxicity evaluation of novel 1,8-acridinedione derivatives bearing phthalimide moiety as potential antitumor agents.

In this study, we aimed to develop hybrid antitumor compounds by synthesizing and characterizing novel N-substituted acrididine-1,8-dione derivatives, designed as hybrids of phthalimide and acridine-1,8-diones. We employed a three-step synthetic strategy and characterized all compounds using IR, 1H NMR, 13C NMR, and LC-MS. The cytotoxicity and antitumor activity of five compounds (8c, 8f, 8h, 8i, and 8L) against four cancer cell lines (H460, A431, A549, and MDA-MB-231) compared to human skin fibroblast cells were evaluated. Among the synthesized compounds, compound 8f showed promising activity against skin and lung cancers, with favorable IC50 values and selectivity index. The relative changes in mRNA expression levels of four key genes (p53, TOP2B, p38, and EGFR) in A431 cells treated with the five synthesized compounds (8c, 8f, 8h, 8i, and 8L) were also investigated. Additionally, molecular docking studies revealed that compound 8f exhibited high binding affinity with TOP2B, p38, p53, and EGFR, suggesting its potential as a targeted anticancer therapy. The results obtained indicate that N-substituted acrididine-1,8-dione derivatives have the potential to be developed as novel antitumor agents with a dual mechanism of action, and compound 8f is a promising candidate for further investigation.

Plant Regulation Functions of Novel Phthalimide Compounds Based on AtPYL2.

Novel agents contain the structure of phthalimide, which has antibacterial, insecticidal, and herbicidal activities. Recently, studies reported that these compounds can bind to plant hormone receptors and play important regulatory roles. In this study, the functions of agents were studied with in vitro and in vivo assays. The abscisic acid (ABA) receptor pyrabactin resistant-like 2 (PYL2) protein in Arabidopsis thaliana was expressed, purified, and crystallized; the analysis results of the crystal structure showed three AtPYL2 subunits in each asymmetric unit. The affinity of compounds Z1-Z11 to the AtPYL2 protein was tested by microscale thermophoresis (MST) and then verified by isothermal titration calorimetry (ITC). Furthermore, the binding pockets were found using molecular docking to verify the target relationships. Relevant in vivo assays for seed germination and a root growth assay were conducted, with the plant samples being treated with target compounds. The results show that the compounds Z3, Z5, and Z10 target AtPYL2 and that the dissociation constants for binding by MST were 3.59, 3.54, and 3.97 µmol/L, respectively, among them, and the molecular docking results showed that compounds Z3, Z5, and Z10 formed hydrophobic interactions with amino acid residues through hydrogen or halogen bonding. This highlights their potential as an ABA receptor protein agonist. On the other hand, in vivo, compounds Z3, Z5, and Z10 had different inhibitory effects on seed germination, with compound Z5 inhibiting the root growth of A. thaliana and compound Z10 affecting root growth. In conclusion, these compounds could regulate plant growth and could be further developed as new plant-regulating agents.

Molecular docking and in vitro antibacterial activity of chiral phthalimide on ESBL producing gram negative bacteria.

Antibiotic resistance is tricky enemy that challenges our healthcare system. It is a stealthy, adaptive and ever evolving opponent, which can take years to develop but can spread like wildfire. In this study, derivatives of chiral phthalimides were developed with this aim to control the growth of resistant strains of Klebsiella pneumonia, Escherichia coli and Pseudomonas aeruginosa by targeting their resistance causing proteins and explore their binding interaction focal points through computational docking. Total 8 novel chiral phthalimides were synthesized and its antibiogram analysis was done on Muller-Hinton Agar by disc diffusion method. Cytotoxicity studies were made to check efficacy of tested compounds on human RBCs and monitor release of hemoglobin absorbance at 540nm. By using in silico molecular approach, crystal structure of target protein was retrieved from Protein Data Bank and docked through Autodock vina and PyRx. The obtained results revealed that seven out of eight compounds have active inhibitory effects against virulent strains. Minimum Inhibitory Concentration (MIC) was measured for most potent compounds i.e., 2-(1,3-dioxoisoindolin-2-yl)-3-(4-hydroxyphenyl) propanoic acid (compound 7) and 3-(1,3-dioxoisoindolin-2-yl) propanoic acid (compound 8). Docking studies displayed a report of highest affinity binding points i.e., amino acids LYS315, ALA318, TYR150, THR262, HIS314 and ARG148 for compound 7 while ALA 318, LYS 315, ARG14 and ILE291 for compound 8.

Phthalimide as a versatile pharmacophore scaffold: Unlocking its diverse biological activities.

Phthalimide, a pharmacophore exhibiting diverse biological activities, holds a prominent position in medicinal chemistry. In recent decades, numerous derivatives of phthalimide have been synthesized and extensively studied for their therapeutic potential across a wide range of health conditions. This comprehensive review highlights the latest developments in medicinal chemistry, specifically focusing on phthalimide-based compounds that have emerged within the last decade. These compounds showcase promising biological activities, including anti-inflammatory, anti-Alzheimer, antiepileptic, antischizophrenia, antiplatelet, anticancer, antibacterial, antifungal, antimycobacterial, antiparasitic, anthelmintic, antiviral, and antidiabetic properties. The physicochemical profiles of the phthalimide derivatives were carefully analyzed using the online platform pkCSM, revealing the remarkable versatility of this scaffold. Therefore, this review emphasizes the potential of phthalimide as a valuable scaffold for the development of novel therapeutic agents, providing avenues for the exploration and design of new compounds.

Carbonic anhydrase inhibitory activity of phthalimide-capped benzene sulphonamide derivatives.

A series of phthalimide-capped benzene sulphonamides (1-22) reported by our group for dengue protease inhibitory activity have been evaluated for their carbonic anhydrase (hCA, EC 4.2.1.1) inhibitory activity against hCA I, hCA II. Compounds 1, 3, 10, and 15 showed hCA I inhibition, whereas 1, 4, and 10 showed hCA II inhibition at nanomolar concentrations. Among these compounds, 1 displayed potent inhibitory activity against the hCA I (Ki = 28.5 nM) and hCA II (Ki = 2.2 nM), being 10 and 6 times more potent than acetazolamide, a standard inhibitor (Ki = 250 nM and 12 nM), respectively. Furthermore, this compound displayed 14-fold selectivity towards the hCA II isoform compared to hCA I. Molecular docking and MD simulations were performed to understand the atomic level interactions responsible for the selectivity of compound 1 towards hCA II.

Design, synthesis, in vitro anti-α-glucosidase evaluations, and computational studies of new phthalimide-phenoxy-1,2,3-triazole-N-phenyl (or benzyl) acetamides as potential anti-diabetic agents.

An important target in the treatment of type 2 diabetes is α-glucosidase. Inhibition of this enzyme led to delay in glucose absorption and decrease in postprandial hyperglycemia. A new series of phthalimide-phenoxy-1,2,3-triazole-N-phenyl (or benzyl) acetamides 11a-n were designed based on the reported potent α-glucosidase inhibitors. These compounds were synthesized and screened for their in vitro inhibitory activity against the latter enzyme. The majority of the evaluated compounds displayed high inhibition effects (IC50 values in the range of 45.26 ± 0.03-491.68 ± 0.11 µM) as compared to the positive control acarbose (IC50 value = 750.1 ± 0.23 µM). Among this series, compounds 11j and 11i represented the most potent α-glucosidase inhibitory activities with IC50 values of 45.26 ± 0.03 and 46.25 ± 0.89 µM. Kinetic analysis revealed that the compound 11j is a competitive inhibitor with a Ki of 50.4 µM. Furthermore, the binding interactions of the most potent compounds in α-glucosidase active site were studied through molecular docking and molecular dynamics. The latter studies confirmed the obtained results through in vitro experiments. Furthermore, in silico pharmacokinetic study of the most potent compounds was also performed.

Preparation, spectroscopic, X-ray crystallographic, DFT, antimicrobial and ADMET studies of N-[(4-flourophenyl)sulfanyl]phthalimide.

N-[(4-Fluorophenyl)sulfanyl]phthalimide (C14H8FNO2S, FP) was synthesized and characterized using X-ray crystallography. It was then investigated via quantum chemical analysis using the density functional theory (DFT) approach, as well as spectrochemically using FT-IR and 1H and 13C NMR spectroscopy, and elemental analysis. The observed and stimulated spectra are in very good agreement for the DFT method. The in vitro antimicrobial activity of FP against three Gram-positive bacteria, three Gram-negative bacteria and two fungi were determined using the serial dilution method, and FP showed the highest antibacterial activity against E. coli, with a MIC of 128 µg ml-1. Druglikeness, ADME (absorption, distribution, metabolism and excretion) and toxicology studies were carried out to theoretically examine the drug properties of FP.

Folpet promotes apoptosis of bovine mammary epithelial cells via disruption of redox homeostasis and activation of MAPK cascades.

Folpet, a phthalimide fungicide, is an agrochemical used to prevent fungal diseases in several crops. The toxicity of folpet has been demonstrated in Cyprinus carpio, pigs, and the human respiratory system. However, despite the possibilities of ingestion of folpet through feed, detrimental influences of folpet on dairy cattle have not been documented. Thus, this study aimed to record the harmful effects of folpet on the bovine mammary system and milk production using mammary epithelial cells (MAC-T cells), which play an essential role in the maintenance of yield and quality of milk production. In this study, we first confirmed that folpet exhibited cytotoxicity against MAC-T cells in both 2D and 3D cultures. Folpet treatment caused apoptosis, dysregulated intracellular calcium levels, and mitochondrial membrane potential, leading to cell death. We further demonstrated the induction of oxidative stress upon folpet treatment by assessing reactive oxygen species (ROS) content and lipid peroxidation in MAC-T cells. ROS generation following folpet treatment induced activation of MAPK cascades, including ERK1/2, JNK, and p38 signaling. This is the first report highlighting the detrimental impacts of folpet on bovine mammary glands and, consequently, the dairy industry by elucidating intracellular mechanisms using MAC-T cells.

In vivo Analgesic Activity of New N-arylphthalimides Derivatives in Mice.

BACKGROUND: A series of phthalimides related to thalidomide have been studied for analgesic activity in the formalin test. The formalin test was performed in mice in a nociceptive pattern to evaluate analgesic activity. METHODS: In this study, nine derivatives of phthalimides were evaluated in terms of exerting analgesic effects in mice. They exerted significant analgesic effects compared to indomethacin and negative control. These compounds were synthesized and characterized by TLC, followed by IR and H1NMR in the previous studies. Two distinct periods of high licking activity were used to analyze both acute and chronic pain. All compounds were compared with indomethacin and carbamazepine as positive control and vehicle as a negative control. RESULTS: All of the tested compounds exhibited significant analgesic activity in both the first and second phases of the test compared to the control group (DMSO), although they did not show more activity than the reference drug (indomethacin) but were comparable to indomethacin. CONCLUSION: This information may be useful in the development of a more potent phthalimide as an analgesic agent that acts as a sodium channel blocker and COX inhibitor.

Discovery of novel VEGFR2-TK inhibitors by phthalimide pharmacophore based virtual screening, molecular docking, MD simulation and DFT.

Currently, numerous potent chemotherapeutic agents are available in the market but most of them show poor pharmacokinetics, lethal effects and drug resistance during their enduring use. The increased cancer cases, deaths and need of better treatment stimulates us to give newer lifesaving anticancer drugs. The phthalimide derivatives are structurally diverse and exert potential anticancer activity. In this regard, the 3D QSAR Pharmacophore model was developed and validated using fifty-eight phthalimide derivatives. The validation parameters corroborated the reliability and statistical robustness of CEASER Hypo 1. Three databases-NCI Open, Drug Bank, and Asinex were submitted to ADMET and drug-like filtering; 117893 drug-like compounds were mapped on CEASER Hypo 1; and 362 hits with IC50 <1 µM were discovered. These hits were docked on VEGFR2-TK, and in the form of results fifteen hits exhibited greater affinity than sorafenib. The top lead ASN 03206926 was subjected for MD simulation (100 ns) and RMSD, Rg, RMSF, number of hydrogen bonds, and SASA verified that the complex was stable, rigid and highly compact. Results demonstrated GLU885, PHE918, CYS919, LYS920, HIS1026, CYS1045, ASP1046 are the essential residues for favourable interactions. The binding free energy calculations support the affinity and stability revealed by docking and MD simulation. The DFT calculations, negative binding energy and lower HOMO-LUMO band gap revealed that the process is spontaneous and ASN 03206926 is very reactive. Following extensive analysis we suggest that the ASN 03206926 might be employed as a new VEGFR2-TK inhibitor for the treatment of breast and VEGFR2-TK associated cancers.Communicated by Ramaswamy H. Sarma.

Novel N-α-amino acid spacer-conjugated phthalimide-triazine derivatives: synthesis, antimicrobial and molecular docking studies.

To design and develop novel antimicrobial agents, a series of phthalimide-triazine-based derivatives (6a-6e) were synthesized, characterized and evaluated for their potential antibacterial activities. The compounds were prepared through reaction of 6-phenyl-1,3,5-triazine-2,4-diamine with phthalimide moiety containing aliphatic amino acid. Structural analysis of the synthesized compounds was carried out by various characterization techniques such as FT-IR, 1H and 13C-NMR and mass spectroscopy. After the confirmation of the structure, the antibacterial screening of the synthesized compounds was performed against two strains of Gram-positive (Staphylococcus aureus, and Bacillus subtilis) and two strains of Gram-negative (Escherichia coli and Salmonella enteritidis) bacteria. The results of antimicrobial activity showed that compound 6d was the most active against all the tested strains of microorganisms with the MIC value 1.25 µg/µl. The synthesized compounds were docked into the binding sites of E. coli-DNA gyrase B and S. aureus-DNA gyrase complex to explore their theoretically binding mode and possible interactions of these ligands with these two targets. Docking study showed the importance of both hydrogen bonding and hydrophobic interactions as a key interaction with the targets. Based on the obtained results, the hybrid derivatives of triazine and phthalimide could be regarded as efficient candidates for further molecular developments of antimicrobial agents.

"In silico identification of ethoxy phthalimide pyrazole derivatives as IL-17A and IL-18 targeted gouty arthritis agents".

Two proinflammatory cytokines, IL17A and IL18, are observed to be elevated in the serum of gout patients and they play a crucial role in the development and worsening of inflammation, which has severe effects. In present study, we have combined molecular docking, molecular dynamics studies and MM-PBSA analysis to study the effectiveness of ethoxy phthalimide pyrazole derivatives (series 3a to 3e) as potential inhibitors against cytokines IL17A and IL18 as a druggable targets. The binding energy of the docked series ranges from -13.5 to -10.0 kcal/mol and extensively interacts with the amino acids in the active pocket of IL17A and IL18. Compound 3e had the lowest binding energy with IL17A at -12.6 kcal/mol compared to control allopurinol (3.32 kcal/mol). With IL18, compound 3a seems to have the lowest binding energy of -9.6 kcal/mol compared to control allopurinol (3.18 kcal/mol). In MD simulation studies, compound 3a forms a stable and energetically stabilized complex with the target protein. Depending on properties of the bound IL17A-3a and IL18-3a complexes was compared by means of MM-PBSA analysis. These derivatives can be used as a scaffold to develop promising IL17A and IL18 inhibitors to assess their potential for gouty arthritis and other related diseases. Communicated by Ramaswamy H. Sarma.

Synthesis of 2-(2-(4-thioxo-3H-1,2-dithiole-5-yl) phenoxy)ethyl)isoindole-1,3-thione, a novel hydrogen sulfide-releasing phthalimide hybrid, and evaluation of its activity in models of inflammatory pain.

Hydrogen sulfide (H2S) is a gaseous mediator that modulates several physiological and pathological processes. Phthalimide analogues, substances that have the phthalimide ring in the structure, belong to the group of thalidomide analogues. Both H2S donors and phthalimide analogues exhibit activities in models of inflammation and pain. As molecular hybridization is an important strategy aiming to develop drugs with a better pharmacological profile, in the present study we synthesized a novel H2S-releasing phthalimide hybrid, 2-(2-(4-thioxo-3H-1,2-dithiole-5-yl) phenoxy)ethyl)isoindole-1,3-thione (PTD-H2S), and evaluated its activity in models of inflammatory pain in mice. Per os (p.o.) administration of PTD-H2S (125 or 250 mg/kg) reduced mechanical allodynia induced by carrageenan and lipopolysaccharide. Intraperitoneal (i.p.) administration of PTD-H2S (25 mg/kg), but not equimolar doses of its precursors 5-(4-hydroxyphenyl)-3H-1,2-dithiole-3-thione (14.2 mg/kg) and 2-phthalimidethanol (12 mg/kg), reduced mechanical allodynia induced by lipopolysaccharide. The antiallodynic effect induced by PTD-H2S (25 mg/kg, i.p.) was more sustained than that induced by the H2S donor NaHS (8 mg/kg, i.p.). Previous administration of hydroxocobalamin (300 mg/kg, i.p.) or glibenclamide (40 mg/kg, p.o.) attenuated PTD-H2S antiallodynic activity. In conclusion, we synthesized a novel H2S-releasing phthalimide hybrid and demonstrated its activity in models of inflammatory pain. PTD-H2S activity may be due to H2S release and activation of ATP-sensitive potassium channels. The demonstration of PTD-H2S activity in models of pain stimulates further studies aiming to evaluate H2S-releasing phthalimide hybrids as candidates for analgesic drugs.

Antihyperlipidemic Activity of Glycoconjugated Phthalimides in Mice Submitted to a Model of Dyslipidemia and Insulin Resistance.

Alterations in lipid and lipoprotein metabolism are factors that trigger several negative metabolic complications. Hyperlipidemia is the starting point for the development of comorbidities of the cardiovascular system, such as atherosclerosis. The search for compounds that reduce high levels of total cholesterol and triglycerides has been widely reported in several publications in the literature. Phthalimide derivatives have been extensively researched with various biological actions. In this study we evaluated the antihyperlipidemic ability of three phthalimide derivatives (FGT-2, FGT-3 and FGT-4) on a model of obesity and insulin resistance in mice. The animals were submitted to a hyperlipid diet for 60 days. On the thirtieth day they were treated with phthalimides (20 mg/kg). The positive control group was treated with Simvastatin (20 mg/kg) and the negative control received only the carboxymethylcellulose vehicle. Biochemical and histological analyzes of all groups were analyzed. The animals treated with phthalimidic derivatives had a reduction in total cholesterol, low density and very low density lipoproteins (LDL-c and VLDL-c), triglycerides and fasting glycemia when compared to the negative control group. The treated animals also showed good results when analyzing the atherogenic indexes Castelli i and II and the ratio Triglycerides/HDL-c. In the oral glucose tolerance test and in the insulin tolerance test, animals treated with phthalimides were more sensitive to the action of the hormone regulating carbohydrate uptake. In the evaluation of the transaminases (AST/ALT), the animals of the group treated with phthalimides presented a lower elevation than the other groups of the experiment, the same observed with the uric acid evaluation. Histological analyzes were performed on liver, kidney, heart and pancreas samples. The groups treated with the compounds FGT-2 and FGT3 presented discrete alterations in the liver and kidney. FGT-4 did not present histological alterations for both tissues and the three phthalimide derivatives did not cause alterations in the other organs. These results suggest that the phthalimides tested can act as antihyperlipidemic agents and have a pleiotropic action, by acting also reducing glycemia in insulin resistance model mimicking diabetes mellitus type 2. These compounds may appear as a new approach in the treatment of obesity and complications, which are multifaceted.