Derivatives 2b Research Articles

Novel phthalocyanines bearing fluoro-methylquinolin substituents: Synthesis, characterization, photophysical and photochemical properties

The novel 4-((6-fluoro-2-methylquinolin-4-yl)oxy)phthalonitrile (3a), 3-((6-fluoro-2-methylquinolin-4-yl)oxy)phthalonitrile (3b), tetra 6-fluoro-2-methylquinolin-4-yl)oxy substituted zinc(II) phthalocyanines (4a and 4b) and their water soluble derivatives (5a and 5b) were prepared. The proposed structures of novel compounds were comfirmed via FT-IR, 1HNMR , UV–Vis and MALDI-TOF mass data. The aggregation tendency, fluorescence quantum yield, singlet oxygen quantum yield and photodegradation measurements were performed to examine the photodynamic therapy potential of both peripherally tetra substituted zinc(II) phthalocyanines (4a and 4b) and the water soluble quaternized tetra substituted zinc(II) phthalocyanines (5a and 5b). The result showed that both the novel tetra 6-fluoro-2-methylquinolin-4-yl)oxy substituted zinc(II) phthalocyanines (4a and 4b) and their water soluble derivatives (5a and 5b) could be used as photosensitizer agents in PDT thanks to their lack of aggregation tendency, having sufficient fluorescence emission for monitoring and produce high amount of singlet oxygen to destroy cancerous tissues and having moderate photostability.

New S-substituted-3-phenyltetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4(3H)-one scaffold with promising anticancer activity profile through the regulation and inhibition of mutated B-RAF signaling pathway.

Novel 3-phenyltetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives were synthesized and screened for their antiproliferative activity against a panel of 60 cancer cell lines. Derivatives 5b, 5f, and 9c showed significant antitumor activity at a single dose with mean growth inhibition of 55.62%, 55.79%, and 71.40%, respectively. These compounds were further investigated against HCT-116, colon cancer cell line, and FHC, normal colon cell line. Compound 9c showed the highest activity with IC50 = 0.904 ± 0.03 µM and SI = 20.42 excelling doxorubicin which scored IC50 = 2.556 ± 0.09 µM and SI = 6.19. Compound 9c was also the most potent against B-RAFWT and mutated B-RAFV600E with IC50 = 0.145 ± 0.005 and 0.042 ± 0.002 µM, respectively in comparison with vemurafenib with IC50 = 0.229 ± 0.008 and 0.038 ± 0.001 µM, respectively. The cell cycle analysis showed that 9c increased the cell population and induced an arrest in the cell cycle of HCT-116 cancer cells at the G0-G1 stage with 1.23-fold. Apoptosis evaluation showed that compound 9c displayed an 18.18-fold elevation in total apoptosis of HCT-116 cancer cells in comparison to the control. Compound 9c increased the content of caspase-3 by 3.52-fold versus the control. A molecular modeling study determined the binding profile and interaction of 9c with the B-RAF active site.

Synthesis and Bioevaluation of New Stable Derivatives of Chrysin-8-C-Glucoside That Modulate the Antioxidant Keap1/Nrf2/HO-1 Pathway in Human Macrophages

Background/Objectives: The beneficial effects of the flavonoid chrysin can be reduced by its poor oral bioavailability. It has been shown that chrysin-8-C-glucoside (1) has a better absorption capability. The aim of this study was to evaluate the antioxidant and anti-inflammatory activity of this glucoside, as well as the respective hexa-acetate derivative 1a and the hexa-ethyl carbonate derivative 1b since the inclusion of moieties in bioactive molecules may increase or modify their biological effects. Methods: THP-1 macrophages were used to determine the viability in the presence of chrysin derivatives, and non-cytotoxic concentrations were selected. Subsequently, lipopolysaccharide (LPS)-induced reactive oxygen species (ROS) production and inflammatory mediators were examined. The involvement of chrysin derivatives with the Keap1 and Nrf2 antioxidant system was determined by docking and Western blotting studies. Results: Our data demonstrated, for the first time, that pretreatment with the three compounds caused a significant reduction in LPS-induced reactive oxygen species (ROS) production and pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and interleukin 1β (IL-1β) levels, as well as in cyclooxygenase 2 (COX-2) expression. The mechanisms underlying these protective effects were related, at least in part, to the competitive molecular interactions of these phenolic compounds with Kelch-like ECH-associated protein 1 (Keap1)–nuclear factor erythroid 2-related factor 2 (Nrf2), which would allow the dissociation of Nrf2 and its translocation into the nucleus and the subsequent up-regulation of hemo-oxygenase 1 (HO-1) expression. Conclusions: Compared to the 8-C-glucoside parent chrysin, compound 1a exhibited the strongest antioxidant and anti-inflammatory activity. We hypothesized that the incorporation of an acetate group (1a) may reduce its polarity and, thus, increase membrane permeability, leading to better pharmacological activity. These findings support the potential use of these phenolic compounds as Nrf2 activators against oxidative-stress-related inflammatory diseases.

Chemical Upcycling of Expired Pharmaceuticals as a Source of Value-Added Chemicals for Organic Synthesis and Medicinal Chemistry.

Pharmaceutical and veterinary products are a class of contaminants of emerging concern, and their presence in the environment is due to continuous and incorrect disposal. Environmental scientists have been accumulating data on their adverse effects on animal populations since toxicological effects on wildlife were first published. Therefore, recycling strategies are needed. Valuable active ingredients can be extracted from expired pharmaceuticals and recycled according to various strategies. In an effort to reveal the potential of the chemical upcycling of expired pharmaceuticals, the active ingredients gabapentin and pregabalin were extracted and used as starting materials to prepare a small collection of promising substrates endowed with functionalities and structural three-dimensionality. Gabapentin 1 was transformed into aminoalcohol 3, spiroamine 4, and the bioactive azaspirolactam 5. The lactam analog 6 was synthesized from pregabalin 2. Due to the biological profile of 5 and the structural similarity of the N-alkylated derivatives 5l and 6b with the drug piracetam, a collection of potentially bioactive structural analogs 5a-l and 6a-b were also prepared. Simple extraction, synthesis, and purification procedures were used as a means of chemical and economic revaluation, resulting in moderate to good yields at a low cost.

Anti-Diabetic Activities and Molecular Docking Studies of Aryl-Substituted Pyrazolo[3,4-b]pyridine Derivatives Synthesized via Suzuki Cross-Coupling Reaction.

Pyrazolo[3,4-b]pyridine scaffolds have been heavily exploited in the development of nitrogen-containing heterocycles with numerous therapeutic applications in the field of medicinal and pharmaceutical chemistry. The present work describes the synthesis of eighteen biaryl pyrazolo[3,4-b]pyridine ester (6a-i) and hydrazide (7a-i) derivatives via the Suzuki cross-coupling reaction. These derivatives were subsequently screened for their therapeutic potential to inhibit the diabetic α-amylase enzyme, which is a key facet of the development of anti-diabetic agents. Initially, the ethyl 4-(4-bromophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate 4 was synthesized through a modified Doebner method under solvent-free conditions, providing an intermediate for further derivatization with a 60% yield. This intermediate 4 was subjected to Suzuki cross-coupling, reacting with electronically diverse aryl boronic acids to obtain the corresponding pyrazolo[3,4-b]pyridine ester derivatives (6a-i). Following this, the biaryl ester derivatives (6a-i) were converted into hydrazide derivatives (7a-i) through a straightforward reaction with hydrazine monohydrate and were characterized using 1H-NMR, 13C-NMR, and LC-MS spectroscopic techniques. These derivatives were screened for their α-amylase inhibitory chemotherapeutic efficacy, and most of the biaryl ester and hydrazide derivatives demonstrated promising amylase inhibition. In the (6a-i) series, the compounds 6b, 6c, 6h, and 6g exhibited excellent inhibition, with almost similar IC50 values of 5.14, 5.15, 5.56, and 5.20 μM, respectively. Similarly, in the series (7a-i), the derivatives 7a, 7b, 7c, 7d, 7f, 7g, and 7h displayed excellent anti-diabetic activities of 5.21, 5.18, 5.17, 5.12, 5.10, 5.16, and 5.19 μM, respectively. These in vitro results were compared with the reference drug acarbose (IC50 = 200.1 ± 0.15 μM), demonstrating better anti-diabetic inhibitory activity in comparison to the reference drug. The in silico molecular docking study results were consistent with the experimental biological findings, thereby supporting the in vitro pharmaceutical efficacy of the synthesized derivatives.

Exploring Acyl Thiotriazinoindole Based Pharmacophores: Design, Synthesis, and SAR Studies with Molecular Docking and Biological Activity Profiling against Urease, α-amylase, α-glucosidase, Antimicrobial, and Antioxidant Targets.

A diminutive chemical library of acyl thiotriazinoindole (ATTI) based bioactive scaffolds was synthesized, instigated by taking the economical starting material Isatin, through a series of five steps. Isatin was first nitrated followed by the attachment of pentyl moiety via nucleophilic substitution reaction. The obtained compound was reacted with thiosemicarbazide to obtain thiosemicarbazone derivative, which was eventually cyclized using basic conditions in water as solvent. Finally, the reported series was obtained through reaction of nitrated thiotriazinoindole moiety with differently substituted phenacyl bromides. The synthesized compounds were characterized using NMR spectroscopy and elemental analysis. Finally, the synthesized motifs were scrutinized for their potential to impede urease, α-glucosidase, DPPH, and α-amylase. Compound 5h with para cyano group manifested the most pivotal biological activity among all, displaying IC50 values of 29.7 ± 0.8, 20.5 ± 0.5 and 36.8 ± 3.9µM against urease, α-glucosidase, and DPPH assay, respectively. Simultaneously, for α-amylase compound 5g possessing a p-CH3 at phenyl ring unfolded as most active, with calculated IC50 values 90.3 ± 1.1µM. The scaffolds were additionally gauged for their antifungal and antibacterial activity. Among the tested strains, 5d having bromo as substituent exhibited the most potent antibacterial activity, while it also demonstrated the highest potency against Aspergillus fumigatus. Other derivatives 5b, 5e, 5i, and 5j also exhibited dual inhibition against both antibacterial and antifungal strains. The interaction pattern of derivatives clearly displayed their SAR, and their docking scores were correlated with their IC50 values. In molecular docking studies, the importance of interactions like hydrogen bonding was further asserted. The electronic factors of various substituents engendered variety of interactions between the ligands and targets implying their importance in the structures of the synthesized heterocyclic scaffolds. To conclude, the synthesized compounds had satisfactory biological activity against various important targets. Further studies are therefore encouraged by attachment of different substitutions in the structure at various positions to enhance the activity of these compounds.

Phytotoxic and Cytogenetic Assessment of Glycerol Triazole Derivatives in Model Plants and Weeds.

Weed invasion represents a challenge for farmers, who typically manage it with herbicides. However, this approach raises concerns about environmental and human health, as well as increasing resistance in these plants with continued use. Therefore, exploring alternative methods, such as heterocyclic compounds, triazoles, is essential due to their biological and environmental relevance. This study aimed to evaluate the effects of twelve 1,2,3-triazoles on the germination and early development of Lactuca sativa, Bidens pilosa, and Lolium multiflorum, as well as their impact on cell division in the cells of L. sativa. Triazole derivatives 4a, 4b, 4c, 4g, 4h, 4i, 4k, and 4l exhibited phytotoxicity, showing varying levels of inhibition in germination, germination speed index, and root growth. Chlorinated compounds were the most detrimental to lettuce development. B. pilosa was notably affected by compounds 4h, 4i, 4k, and 4l, while L. multiflorum responded most to triazoles 4c and 4l, with effectiveness comparable to that of the herbicide glyphosate. All derivatives, except 4l, exhibited aneugenic mechanisms of action, and 4a, 4b, 4c, 4e, 4f, and 4g showed clastogenic effects. This study demonstrated the potential of triazoles as effective agents against weed growth, with mechanisms that warrant further investigation for agricultural applications.

Benzylhydroxamic acids as inhibitors of insulin regulated aminopeptidase (IRAP)

With the objective of finding new classes of cognitive enhancers with potential for the treatment of neurodegenerative disorders, such as Alzheimer's disease, small molecule inhibitors of insulin-regulated aminopeptidase (IRAP) were designed and synthesized. IRAP is a member of the M1 family of zinc aminopeptidases and is abundantly expressed in areas of the brain associated with cognition, such as the amygdala, hippocampus and cerebral cortex. IRAP inhibitors were previously shown to enhance memory and learning in animal models. A comprehensive high throughput screening of 400,000 small molecules from the European Lead Factory library provided a series of 50 promising compounds in a qualified hit list (QHL). More than 30 IRAP inhibitors with an IC50 below 3.5 μM were identified. Herein, selected compounds from this QHL were assayed for solubility and permeability. Most of the selected compounds displayed good solubility, but further permeability studies on the best compounds revealed low blood brain barrier (BBB) permeability and high efflux in cells overexpressing P-gp pumps, rendering them less promising as starting points in drug discovery processes. Two compounds from the QHL were prioritized for further structural optimization; the pyridyl-substituted isoxazole 1a (QHL27) and the benzylhydroxamic acid derivative 1b (QHL1), both demonstrating fair BBB permeability and no indication of efflux. While our attempts to improve the isoxazole derivative 1a were not fruitful, a structural modification of 1b to provide the chloro-substituted benzylhydroxamic acid 14b resulted in a ten-fold improvement of the IRAP inhibition with an IC50 value of 60 nM. The binding modes of 1b and 14b were determined by free energy perturbation (FEP) analysis performed on candidate docking poses, determining a binding mode that accurately explained the experimental SAR. Further FEP studies of compound 14b suggested that it exhibits selectivity towards IRAP over Aminopeptidase N (APN), indicating its potential for targeted therapeutic applications.

Synthesis and Antimicrobial Activity of (E)-1-Aryl-2-(1H-tetrazol-5-yl)acrylonitrile Derivatives via [3+2] Cycloaddition Reaction Using Reusable Heterogeneous Nanocatalyst under Microwave Irradiation.

The magnetically recoverable heterogeneous Fe2O3@cellulose@Mn nanocomposite was synthesized by a stepwise fabrication of Mn nanoparticles on cellulose-modified magnetic Fe2O3 nanocomposites, and the morphology of the nanocomposite was characterized through advanced spectroscopic techniques. This nanocomposite was investigated as a heterogeneous catalyst for the synthesis of medicinally important tetrazole derivatives through Knoevenagel condensation between aromatic/heteroaromatic aldehyde and malononitrile followed by [3+2] cycloaddition reaction with sodium azide. Thirteen potent (E)-1-aryl-2-(1H-tetrazol-5-yl)acrylonitrile derivatives are reported in this paper with very high yields (up to 98%) and with excellent purity (as crystals) in a very short period (3 min @ 120 W) using microwave irradiation. The present procedure offers several advantages over recent protocols, including minimal catalyst loading, quick reaction time, and the utilization of an eco-friendly solvent. Furthermore, the synthesized (E)-1-aryl-2-(1H-tetrazol-5-yl)acrylonitrile derivatives (4b, 4c, and 4m) are shown to have excellent resistance against various fungal strains over bacterial strains as compared to the standard drugs Cefixime (4 μg/mL) and Fluconazole (2 μg/mL).

Bioisosteric replacement of the carboxylic acid group in Hepatitis-C virus NS5B thumb site II inhibitors: phenylalanine derivatives

Hepatitis C virus (HCV) is a global health concern and the NS5B RNA-dependent RNA polymerase (RdRp) of HCV is an attractive target for drug discovery due to its role in viral replication. This study focuses on NS5B thumb site II inhibitors, specifically phenylalanine derivatives, and explores bioisosteric replacement and prodrug strategies to overcome limitations associated with carboxylic acid functionality. The synthesized compounds demonstrated antiviral activity, with compound 6d showing the most potent activity with an EC50 value of 3.717 μM. The hydroxamidine derivatives 7a-d showed EC50 values ranging from 3.9 μM to 11.3 μM. However, the acidic heterocyclic derivatives containing the oxadiazolone (8a-d) and oxadiazolethione (9a-d) rings did not exhibit measurable activity. A methylated heterocycle 10b showed a hint of activity at 8.09 μM. The pivaloyloxymethyl derivatives 11a and 11b did not show antiviral activity. Further studies are warranted to fully understand the effects of these modifications and to explore additional strategies for developing novel therapeutic options for HCV.

Discovery of novel thiazole derivatives containing pyrazole scaffold as PPAR-γ Agonists, α-Glucosidase, α-Amylase and COX-2 inhibitors; Design, synthesis and in silico study

A novel series of thiazole derivatives with pyrazole scaffold 16a-l as hybrid rosiglitazone/celecoxib analogs was designed, synthesized and tested for its PPAR-γ activation, α-glucosidase, α-amylase and COX-2 inhibitory activities. Regarding the anti-diabetic activity, all compounds were assessed in vitro against PPAR-γ activation, α-glucosidase and α-amylase inhibition in addition to in vivo hypoglycemic activity (one day and 15 days studies). Compounds 16b, 16c, 16e and 16 k showed good PPAR-γ activation (activation % ≈ 72–79 %) compared to that of the reference drug rosiglitazone (74 %). In addition, the same derivatives 16b, 16c, 16e and 16 k showed the highest inhibitory activities against α-glucosidase (IC50 = 0.158, 0.314, 0.305, 0.128 μM, respectively) and against α-amylase (IC50 = 32.46, 23.21, 7.74, 35.85 μM, respectively) compared to the reference drug acarbose (IC50 = 0.161 and 31.46 μM for α-glucosidase and α-amylase, respectively). The most active derivatives 16b, 16c, 16e and 16 k also revealed good in vivo hypoglycemic effect comparable to that of rosiglitazone. In addition, compounds 16b and 16c had the best COX-2 selectivity index (S.I. = 18.7, 31.7, respectively) compared to celecoxib (S.I. = 10.3). In vivo anti-inflammatory activity of the target derivatives 16b, 16c, 16e and 16 k supported the results of in vitro screening as the derivatives 16b and 16c (ED50 = 8.2 and 24 mg/kg, respectively) were more potent than celecoxib (ED50 = 30 mg/kg). In silico docking, ADME, toxicity, and molecular dynamic studies were carried out to explain the interactions of the most active anti-diabetic and anti-inflammatory compounds 16b, 16c, 16e and 16 k with the target enzymes in addition to their physiochemical parameters.

Thiophene-Linked 1,2,4-Triazoles: Synthesis, Structural Insights and Antimicrobial and Chemotherapeutic Profiles.

The reaction of thiophene-2-carbohydrazide 1 or 5-bromothiophene-2-carbohydrazide 2 with various haloaryl isothiocyanates and subsequent cyclization by heating in aqueous sodium hydroxide yielded the corresponding 4-haloaryl-5-(thiophen-2-yl or 5-bromothiophen-2-yl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 5a-e. The triazole derivatives 5a and 5b were reacted with different secondary amines and formaldehyde solution to yield the corresponding 2-aminomethyl-4-haloaryl-2,4-dihydro-3H-1,2,4-triazole-3-thiones 6a-e, 7a-e, 8, 9, 10a and 10b in good yields. The in vitro antimicrobial activity of compounds 5a-e, 6a-e, 7a-d, 8, 9, 10a and 10b was evaluated against a panel of standard pathogenic bacterial and fungal strains. Compounds 5a, 5b, 5e, 5f, 6a-e, 7a-d, 8, 9, 10a and 10b showed marked activity, particularly against the tested Gram-positive bacteria and the Gram-negative bacteria Escherichia coli, and all the tested compounds were almost inactive against all the tested fungal strains. In addition, compounds 5e, 6a-e, 7a-d and 10a exhibited potent anti-proliferative activity, particularly against HepG-2 and MCF-7 cancer cell lines (IC50 < 25 μM). A detailed structural insight study based on the single crystals of compounds 5a, 5b, 6a, 6d and 10a is also reported. Molecular docking studies of the highly active antibacterial compounds 5e, 6b, 6d, 7a and 7d showed a high affinity for DNA gyrase. Meanwhile, the potent anti-proliferative activity of compounds 6d, 6e and 7d may be attributed to their high affinity for cyclin-dependent kinase 2 (CDK2).

Chemical, antimicrobial, antioxidant, and molecular dynamic studies of spiro[chromane-3',2''-thiopyran]-4'-one 1''-oxide and spiro[chromane-3',2''-thiopyran]-4'-one 1'',1''-dioxide

Some of spiro[chromane-3',2''-thiopyran]-4'-ones were oxidized via m-chloroperbenzoic acid and/or hydrogen peroxide to afford the corresponding nine spiro[chromane-3',2''-thiopyran]-4'-one 1''-oxides and three spiro[chromane-3',2''-thiopyran]-4'-one 1'',1''-dioxides, which were confirmed by spectral data (IR, 1H NMR, 13C NMR, MS-ESI, and MS-EI). Whereas, the yield of oxidation using hydrogen peroxide is higher than that of oxidation using m-chloroperbenzoic acid. Moreover, Gram-negative bacteria (Escherichia coli ATCC 25922), and Gram-positive bacteria (Staphylococcus aureus ATCC 6538) were adopted to test the antimicrobial activity of 12 newly synthesized compounds (7a, 8a-c, 9a, 10a-c, 11a, 12a-c). The three sulfoxide derivatives 8b, 10b, and 10c showed antimicrobial activity. Also, antioxidant activity was evaluated for the newly synthesized compounds and shows that, all newly synthesized compounds (7a, 8a-c, 9a, 10a-c, 11a, 12a-c) have antioxidant activity. Molecular dynamic and system stability, Binding interaction mechanism based on binding free energy calculation, Identification of the critical residues responsible for ligands binding, Ligand–residue interaction network profiles, and In silico ADMET properties prediction were studied for the new compounds. The results of molecular dynamic studies were consistent with the in vitro antibacterial and antioxidant activity.

New substituted benzenesulphonamoyl ‘Cys-Gly’ dipeptide carboxamide derivatives: Design, synthesis, characterization and pharmacological studies

Twelve new sulphonamide (Cys-Gly) dipeptide carboxamide derivatives 17a–17l were designed, prepared and characterized through spectroscopic techniques and their pharmacological properties investigated. The molecular docking analyses revealed good interactions of the derivatives with the desired amino residues active pockets. In vitro antimicrobial, in vivo antimalarial, haematological and other related tests (liver and kidney) were also conducted. Compounds 17b exhibited good minimum inhibitory concentration (MIC) results (0.9–11) mg/mL for the studied organisms when compared with ciprofloxacin and fluconazole. Derivatives 17a −17l showed parasitaemia inhibition in the range (31.11–67.78) % on the fourth day after treating the animals with 40 mg/kg of the compounds. Derivative 17b also displayed the highest parasitaemia inhibition (67.78 %) comparable with the standard (Lumenfantrine) 75.27 %. The prepared derivatives showed promising pharmacological properties with regards to hematological, liver and kidney function tests.

Fungicidal activity and molecular docking of glycerol‐derived triazole compounds for controlling coffee leaf rust

AbstractCoffee leaf rust (CLR), caused by Hemileia vastatrix, poses a significant threat to global coffee production, resulting in substantial economic losses. This study explores the effectiveness of triazole derivatives synthesized from glycerol in controlling CLR in conilon coffee (Coffea canephora). In vitro assays evaluated the inhibitory effect of triazole derivatives (4a–4q) at concentrations of 10, 25, 50, 75 and 100 ppm on H. vastatrix urediniospore germination, followed by greenhouse experiments to assess their preventive and curative potential. Preventive and curative sprayings of the four most efficient triazoles were conducted on seedlings inoculated with H. vastatrix at concentrations ranging from 0 to 400 ppm, evaluating severity, sporulation, incubation and latent periods. Triazole derivatives 4b, 4d, 4f and 4o effectively suppressed H. vastatrix urediniospore germination, achieving reductions between 9.9% and 78.8%. In greenhouse trials, these compounds demonstrated preventive efficacy by prolonging incubation and latent periods, reducing sporulation and mitigating rust severity, with triazole 4f exhibiting the highest efficiency. Furthermore, the derivatives showed effectiveness in curative treatments, particularly triazole 4f. Physiological analyses indicated no significant alterations in coffee plant metabolism, suggesting the safety of these compounds for agricultural use. Molecular docking studies elucidated their mechanism of action, suggesting their potential as antifungal agents by interacting with the HvCYP51 enzyme involved in ergosterol biosynthesis. Overall, the study underscores the promising efficacy of glycerol‐derived triazole derivatives in managing CLR, providing sustainable solutions for disease control in agriculture.

Novel multitarget directed ligands inspired by riluzole: A serendipitous synthesis of substituted benzo[b][1,4]thiazepines potentially useful as neuroprotective agents

Riluzole, the first clinically approved treatment for amyotrophic lateral sclerosis (ALS), represents a successful example of a drug endowed with a multimodal mechanism of action. In recent years, different series of riluzole-based compounds have been reported, including several agents acting as Multi-Target-Directed Ligands (MTLDs) endowed with neuroprotective effects. Aiming at identical twin structures inspired by riluzole (2a-c), a synthetic procedure was planned, but the reactivity of the system took a different path, leading to the serendipitous isolation of benzo[b][1,4]thiazepines 3a-c and expanded intermediates N-cyano-benzo[b][1,4]thiazepines 4a-c, which were fully characterized. The newly obtained structures 3a-c, bearing riluzole key elements, were initially tested in an in vitro ischemia/reperfusion injury protocol, simulating the cerebral stroke. Results identified compound 3b as the most effective in reverting the injury caused by an ischemia-like condition, and its activity was comparable, or even higher than that of riluzole, exhibiting a concentration-dependent neuroprotective effect. Moreover, derivative 3b completely reverted the release of Lactate Dehydrogenase (LDH), lowering the values to those of the control slices. Based on its very promising pharmacological properties, compound 3b was then selected to assess its effects on voltage-dependent Na+ and K+ currents. The results indicated that derivative 3b induced a multifaceted inhibitory effect on voltage-gated currents in SH-SY5Y differentiated neurons, suggesting its possible applications in epilepsy and stroke management, other than ALS. Accordingly, brain penetration was also measured for 3b, as it represents an elegant example of a MTDL and opens the way to further ex-vivo and/or in-vivo characterization.

Synthesis of novel imidazole-based compounds via using sonication technique: Influence of chemical reaction manipulation, antiproliferative activity through apoptosis induction, cell migration inhibition, and antioxidant properties

This study presents the synthesis and biological evaluation of a new series of imidazole-based compounds and acyl thiourea derivatives derived from aroyl isothiocyanates, exploring the effects of various reaction conditions on their synthesis. Among the synthesized compounds, four candidates 4a, 4b, 8, and 9 demonstrated significant antiproliferative activities against four cancer cell lines (HepG-2, HCT-116, MCF-7, and PC-3), with IC50 values ranging from 2.89 μM to 22.01 μM. Compounds 4b and 8 were predicted to inhibit cell migration by 67 % and 43 %, respectively, and were further evaluated for their antioxidant activity. Results showed that compound 4b exhibited the highest antioxidant activity with an IC50 of 99.96 μM. Additionally, cell cycle analysis demonstrated that derivatives 4b and 8 exerted antiproliferative effects at the G1 phase. Apoptosis assays revealed that compounds 4b and 8 induced apoptosis in 39.81 % and 44.18 % of cells, respectively, compared to the control.

Development of novel organometallic sulfonamides with N-ethyl or N-methyl benzenesulfonamide units as potential human carbonic anhydrase I, II, IX and XII isoforms' inhibitors: Synthesis, biological evaluation and docking studies

In the search of new cymantrenyl- and ferrocenyl-sulfonamides as potencial inhibitors of human carbonic anhydrases (hCAs), four compounds based on N-ethyl or N-methyl benzenesulfonamide units have been obtained. These cymantrenyl (1a-b) and ferrocenyl (2a-b) derivatives were prepared by the reaction between aminobenzene sulfonamides ([NH2-(CH2)n-(C6H4)-SO2-NH2)], where n = 1, 2) with cymantrenyl sulfonyl chloride (P1) or ferrocenyl sulfonyl chloride (P2), respectively. All compounds were characterized by conventional spectroscopic techniques and cyclic voltammetry. In the solid state, the molecular structures of compounds 1a, 1b, and 2b were determined by single-crystal X–ray diffraction. Biological evaluation as carbonic anhydrases inhibitors were carried out and showed derivatives 1b y 2b present a higher inhibition than the drug control for the Human Carbonic Anhydrase (hCA) II and IX isoforms (KI = 7.3 nM and 5.8 nM, respectively) and behave as selective inhibition for hCA II isoform. Finally, the docking studies confirmed they share the same binding site and interactions as the known inhibitors acetazolamide (AAZ) and agree with biological studies.

A new route to the synthesis of 2-hydrazolyl-4-thiazolidinone hybrids, evaluation of α-glucosidase inhibitory activity and molecular modeling insights

One of the multifactorial worldwide health syndromes is diabetes mellitus which is increasing at a disturbing rate. The inhibition of α-glucosidase, an enzyme that catalyzes starch hydrolysis in the intestine, is one helpful therapeutic approach for controlling hyperglycemia related to type-2 diabetes. To discover α-glucosidase inhibitors, some 2-hydrazolyl-4-thiazolidinone hybrids (3a-e) were synthesized from new one-pot reaction procedures. Next, their chemical structures were confirmed by 1H NMR, 13C NMR, and FT-IR spectra, and elemental analysis technique. Then, the α-glucosidase inhibitory activity of the titled compounds was evaluated. Among them, derivatives 3b and 3c revealed the highest activity against α-glucosidase compared to acarbose as a drug. Enzyme kinetic studies of the most active derivative (3b) indicated a competitive inhibition. Finally, molecular modeling studies were accomplished to describe vital interactions of the most potent compounds (3b and 3c) with the α-glucosidase enzyme.

Development of novel antibiotics derived from pyridazine: Synthesis, spectroscopic characterization, in vitro antimicrobial activity and molecular docking studies

In light of the increasing antibiotic resistance, it is crucial to discover new antimicrobial medications. Pyridazines are frequently investigated in research for the development of new chemical entities with enhanced therapeutic properties. Their structure allows for significant flexibility in the attachment of various functional groups, which is essential for drug discovery.Our work focuses on synthesizing new pyridazine derivatives (7a, 7b, 7c and 7d) through coupling reactions with various amino esters. The structures of these compounds have been analyzed using spectroscopic measurements including 1H, 13C NMR, IR, and mass spectroscopy. The compounds showed positive effects against two bacterial strains: Escherichia coli: ATCC25922 and Staphylococcus aureus: CIP543154. Molecular docking results of the protein 7AZ5 indicated significant affinities with these molecules through hydrogen bonds. Compounds 7a and 7d demonstrated the highest binding energies and the best antimicrobial activity, suggesting their potential as a model for creating novel and potent antimicrobial compounds.