Archiv der Pharmazie

Mannich Curcuminoids as Potent Anticancer Agents ()
A series of novel curcuminoids were synthesised for the first time via a Mannich-3CR/organocatalysed Claisen–Schmidt condensation sequence. Structure–activity relationship (SAR) studies were performed by applying viability assays and holographic microscopic imaging to these curcumin analogues for anti-proliferative activity against A549 and H1975 lung adenocarcinoma cells. The TNFα-induced NF-κB inhibition and autophagy induction effects correlated strongly with the cytotoxic potential of the analogues. Significant inhibition of tumour growth was observed when the most potent analogue 44 was added in liposomes at one-sixth of the maximally tolerated dose in the A549 xenograft model. The novel spectrum of activity of these Mannich curcuminoids warrants further preclinical investigations. Novel Mannich curcuminoids were synthesized and their antiproliferative activities were tested against lung adenocarcinoma cells. Structure–activity relationships and the background of TNFα-induced NF-κB inhibition and autophagy induction were established. The lead compound N-((E)-5-(3-hydroxyphenyl)-2-((E)-3-(3-hydroxyphenyl)acryloyl)-3-oxo-1-phenylpent-4-en-1-yl)acrylamide 44 led to significant tumour size reduction in the A549 xenograft model.
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Three-Component Aminoalkylations Yielding Dihydronaphthoxazine-Based Sirtuin Inhibitors: Scaffold Modification and Exploration of Space for Polar Side-Chains ()
Nonpolar derivatives of heterocyclic aromatic screening hits like the non-selective sirtuin inhibitor splitomicin tend to be poorly soluble in biological fluids. Unlike sp3-rich natural products, flat aromatic compounds are prone to stacking and often difficult to optimize into leads with activity in cellular systems. The aim of this work was to identify anchor points for the introduction of sp3-rich fragments with polar functional groups into the newly discovered active (IC50 = 5 μM) but nonpolar scaffold 1,2-dihydro-3H-naphth[1,2-e][1,3]oxazine-3-thione by a molecular modeling approach. Docking studies were conducted with structural data from crystallized human SIRT2 enzyme. Subsequent evaluation of the in silico hypotheses through synthesis and biological evaluation of the designed structures was accomplished with the aim to discover new SIRT2 inhibitors with improved aqueous solubility. Derivatives of 8-bromo-1,2-dihydro-3H-naphth[1,2-e][1,3]oxazine-3-thione N-alkylated with a hydrophilic morpholino-alkyl chain at the thiocarbamate group intended for binding in the acetyl-lysine pocket of the enzyme appeared to be promising. Both the sulfur of the thiocarbamate and the bromo substituent were assumed to result in favorable hydrophobic interactions and the basic morpholino-nitrogen was predicted to build a hydrogen bond with the backbone Ile196. While the brominated scaffold showed moderately improved activity (IC50 = 1.8 μM), none of the new compounds displayed submicromolar activity. Synthesis and characterization of the new compounds are reported and the possible reasons for the outcome are discussed. The achiral scaffold 1,2-dihydro-3H-naphth[1,2-e][1,3]oxazine-3-thione (IC50 = 5.0 μM) was discovered as a promising starting point for the hunt for new inhibitors of human Sirt2. Decoration with halogen atoms and side-chains with polar head groups was thought to be the strategy of choice for obtaining active derivatives with desirable physicochemical profiles. While the bromination turned out favorable, exploration of a promising binding pocket revealed that hydrophobic interactions would be compulsory here.
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Oxazolo[4,5-b]pyridine-Based Piperazinamides as GSK-3β Inhibitors with Potential for Attenuating Inflammation and Suppression of Pro-Inflammatory Mediators ()
Recent studies reveal that glycogen synthase kinase-3β (GSK-3β) acts as a pro-inflammatory enzyme, and by inhibiting this kinase, inflammation can be controlled. In this regard, a series of 17 piperazine-linked oxazolo[4,5-b]pyridine-based derivatives was synthesized and evaluated for in vitro GSK-3β inhibitory and in vivo anti-inflammatory activity. The compounds 7d, 7e, 7g, and 7c displayed the best GSK-3β inhibitory activity among all the synthesized compounds, with corresponding IC50 values of 0.34, 0.39, 0.47, and 0.53 µM. Among the compounds 7d, 7e, 7g, and 7c examined for in vivo anti-inflammatory activity in the rat paw edema model, compound 7d exhibited maximum inhibition, reducing the paw volume by 62.79 and 65.91% at 3 and 5 h post-carrageenan administration, respectively, in comparison to indomethacin (76.74% at 3 h and 79.54% at 5 h after carrageenan administration). Furthermore, these compounds (7d, 7e, 7g, and 7c) were also found to substantially inhibit pro-inflammatory mediators, i.e., TNF-α, IL-1β, and IL-6, ex vivo in comparison to indomethacin and did not pose any gastric ulceration risk, indicating the potential of this oxazolopyridine scaffold for the development of GSK-3β inhibitors and their application as anti-inflammatory agents. A series of piperazine-linked oxazolo[4,5-b]pyridine-based derivatives was synthesized and evaluated for in vitro glycogen synthase kinase-3β (GSK-3β) inhibitory and in vivo anti-inflammatory activity. Compounds 7d, 7e, 7g, and 7c, which displayed the best GSK-3β inhibitory activity among all the synthesized compounds, were also found to substantially inhibit pro-inflammatory mediators such as TNF-α, IL-1β, and IL-6.
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Benzimidazole Scaffold as Anticancer Agent: Synthetic Approaches and Structure–Activity Relationship ()
Cancer, also known as malignant neoplasm, is a dreadful disease which involves abnormal cell growth having the potential to invade or spread to other parts of the body. Benzimidazole is an organic compound that is heterocyclic and aromatic in nature. It is a bicyclic compound formed by the fusion of the benzene and imidazole ring systems. It is an important pharmacophore and a privileged structure in medicinal chemistry. According to the World Health Organisation (2015 survey), one in six deaths is due to cancer around the globe, accounting for 8.8 million deaths of which 70% of the cases were from low- and middle-income countries. In the efforts to develop suitable anticancer drugs, medicinal chemists have focussed on benzimidazole derivatives. This review article covers the current development of benzimidazole-based anticancer agents along with the synthetic approaches and structure–activity relationships (SAR). In order to develop suitable anticancer drugs, medicinal chemists have focussed on derivatives of benzimidazole, a bicyclic compound formed by the fusion of the benzene and imidazole ring systems. This review article covers the current development of benzimidazole-based anticancer agents along with the synthetic approaches and structure–activity relationships.
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Design, Synthesis, and Biological Evaluation of Coumarin–Triazole Hybrid Molecules as Potential Antitumor and Pancreatic Lipase Agents ()
The design, synthesis, and investigation of antitumor and anti-lipase activities of some coumarin–triazole hybrid molecules are reported. The synthesis of these hybrid molecules was performed under microwave irradiation and conventional heating procedures. The newly synthesized hybrid molecules were investigated as inhibitors against four tumor cell lines (BT20 human breast carcinoma, SK-Mel 128 melanoma, DU-145 prostate carcinoma, and A549 lung carcinoma) and porcine pancreatic lipase (PPL). Most of these compounds showed notable antitumor activities against the tested tumor cell lines, and compounds 8i and 8l showed the best anti-lipase activity of 99.30 ± 0.56% and 99.85 ± 1.21%, respectively, at a concentration of 10 μM. Some coumarin–triazole hybrid molecules were designed, synthesized, and tested for their antitumor and anti-lipase activities against four tumor cell lines and porcine pancreatic lipase, respectively. Most of these compounds showed notable antitumor activities against the tested tumor cell lines, and compounds 8i and 8l at 10 µM showed the best anti-lipase activity of 99.30 ± 0.56% and 99.85 ± 1.21%, respectively.
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A Novel Pregabalin Functionalized Salicylaldehyde Derivative Afforded Prospective Pain, Inflammation, and Pyrexia Alleviating Propensities ()
A novel pregabalin derivative named as pregsal ((S,E)-3-(((2-hydroxybenzylidene)amino)methyl)-5-methylhexanoic acid) was synthesized by a simple imination reaction between pregabalin and salicylaldehyde and was evaluated in the in vivo testing paradigms. The compound was characterized by UV, IR, 1H, 13C NMR, HR ESI-MS, and elemental analysis. It was screened (30, 50, 75, and 100 mg/kg) for antinociceptive, anti-inflammatory, and antipyretic activities in relation to pregabalin. The synthesized compound significantly attenuated the tonic acetic acid-induced nociceptive pain (30 mg/kg (P < 0.05), 50 mg/kg (P < 0.01), 75 and 100 mg/kg (P < 0.001)), and thermal-induced hyperalgesia (P < 0.001). These activities were succinctly antagonized (P < 0.05, P < 0.01, P < 0.001) by naloxone and pentylenetetrazole, implicating the involvement of opioidergic and GABAergic mechanisms. The compound also inhibited the temporal inflammatory response and alleviated the yeast-induced pyrexia (P < 0.05, P < 0.01, and P < 0.001). These findings suggest that the synthesized compound possessed prospective pain, inflammation, and pyrexia relieving propensities and therefore may serve as a potential drug candidate for the therapeutic management of chronic pain conditions. Pregsal ((S,E)-3-(((2-hydroxybenzylidene)amino)methyl)-5-methylhexanoic acid) was synthesized by a simple imination reaction between pregabalin and salicylaldehyde and screened for its antinociceptive, anti-inflammatory, and antipyretic activities in relation to pregabalin. The results show that pregsal may serve as a potential drug candidate for the therapeutic management of chronic pain conditions.
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Synthesis and Biological Evaluation of New Combined α/β-Adrenergic Blockers ()
The synthesis, characterization, and pharmacological evaluation of new aryloxyaminopropanol compounds based on substituted (4-hydroxyphenyl)ethanone with alterations in the alkoxymethyl side chain in position 2 and with 2-methoxyphenylpiperazine in the basic part of the molecule are reported. For the in vitro pharmacological evaluation, isolated aorta and atria from normotensive Wistar rats were used. Compared to naftopidil, compounds with ethoxymethyl, propoxymethyl, butoxymethyl, and methoxyethoxymethyl substituent displayed similar α1-adrenolytic potency. Compounds with methoxymethyl, ethoxymethyl, and propoxymethyl substituent caused a significant decrease in both spontaneous and isoproterenol-induced beating of isolated rat atria. Naftopidil and the tested substances containing a butoxymethyl and methoxyethoxymethyl substituent had no effect on the spontaneous or isoproterenol-induced beating. The tested substance that had the most pronounced effect was the compound with a propoxymethyl substituent. Its antihypertensive efficacy was investigated in vivo on spontaneously hypertensive rats (SHRs). The systolic blood pressure was found to be significantly lower in SHRs subjected to the treatment for 2 weeks than in untreated SHRs. Naftopidil had no significant effect. New aryloxyaminopropanol compounds based on substituted (4-hydroxyphenyl)ethanone with alterations in the alkoxymethyl side chain in position 2 and with 2-methoxyphenylpiperazine in the basic part of the molecule were synthesized and pharmacologically evaluated on isolated aorta and atria from normotensive Wistar rats. The substance with the most pronounced effect, bearing a propoxymethyl substituent, was tested for antihypertensive efficacy on spontaneously hypertensive rats.
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Novel NHC Precursors: Synthesis, Characterization, and Carbonic Anhydrase and Acetylcholinesterase Inhibitory Properties ()
Three series of imidazolidinium ligands (NHC precursors) substituted with 4-vinylbenzyl, 2-methyl-1,4-benzodioxane, and N-propylphthalimide were synthesized. N-Heterocyclic carbene (NHC) precursors were prepared from N-alkylimidazoline and alkyl halides. The novel NHC precursors were characterized by 1H NMR, 13C NMR, FTIR spectroscopy, and elemental analysis techniques. The enzymes inhibition activities of the NHC precursors were investigated against the cytosolic human carbonic anhydrase I and II isoenzymes (hCA I and II) and the acetylcholinesterase (AChE) enzyme. The inhibition parameters (IC50 and Ki values) were calculated by spectrophotometric method. The inhibition constants (Ki) were found to be in the range of 166.65–635.38 nM for hCA I, 78.79–246.17 nM for hCA II, and 23.42–62.04 nM for AChE. Also, the inhibitory effects of the novel synthesized NHCs were compared to acetazolamide as a clinical CA isoenzymes inhibitor and tacrine as a clinical cholinergic enzymes inhibitor. Three series of imidazolidinium ligands (NHC precursors) substituted with 4-vinylbenzyl, 2-methyl-1,4-benzodioxane, and N-propylphthalimide were synthesized and their enzyme inhibitory activities were investigated against human carbonic anhydrase I and II (hCA I and II) and acetylcholinesterase, in comparison to acetazolamide as a clinical CA isoenzyme inhibitor and tacrine as a clinical cholinergic enzymes inhibitor.
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New Anti-Seizure (Arylalkyl)azole Derivatives: Synthesis, In Vivo and In Silico Studies ()
(Arylalkyl)azoles are a class of antiepileptic compounds including nafimidone, denzimol, and loreclezole (LRZ). Nafimidone and denzimol are thought to inhibit voltage-gated sodium channels (VGSCs) and enhance γ-aminobutyric acid (GABA)-mediated response. LRZ, a positive allosteric modulator of A-type GABA receptors (GABAARs), was reported to be sensitive to Asn265 of the β2/β3 subunit. Here, we report new N-[1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethylidene]hydroxylamine esters showing anticonvulsant activity in animal models, including the 6-Hz psychomotor seizure test, a model for therapy-resistant partial seizure. We performed molecular docking studies for our active compounds using GABAAR and VGSC homology models. They predicted high affinity to the benzodiazepine binding site of GABAAR in line with the experimental results. Also, the binding mode and interactions of LRZ in its putative allosteric binding site of GABAAR is elucidated. N-[1-(4-Chlorophenyl)-2-(1H-imidazol-1-yl)ethylidene]hydroxylamine esters were prepared and in vivo evaluated for their protective potentials against convulsions induced by the 6-Hz, maximal electroshock, and subcutaneous metrazol methods. While most of the derivatives were active in at least one of the models, compound 4c stood out with an ED50 of 48.85 mg/kg in the 6-Hz test at 0.25 h in mice administered via the intraperitoneal route.
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Synthesis and Evaluation of Thiazolidine Amide and N-Thiazolyl Amide Fluoroquinolone Derivatives ()
In an effort to develop new fluoroquinolones, we synthesized eight compounds and tested them against a panel of bacteria. The design of these compounds was guided by the introduction of the isothiazoloquinolone motif. The three most active compounds in this series, 8–10, demonstrated good antibacterial activity against methicillin-sensitive Staphylococcus aureus and healthcare-acquired methicillin-resistant Staphylococcus aureus (MIC 0.62–6.3 µg/mL). Further, when these three active compounds were tested for their inhibitory effects on bacterial enzymes, compound 9 was the most effective agent exhibiting IC50 values of 33.9 and 116.5 μM in the S. aureus deoxyribonucleic acid (DNA) gyrase supercoiling and topoisomerase IV decatenation assays, respectively. A series of non-carboxylic acid fluoroquinolone analogs containing thiazolidine and N-thiazolyl amides were synthesized. All compounds were evaluated for their in vitro minimum inhibitory concentrations against clinically relevant bacteria. In addition, the three most active compounds were tested for their enzyme-inhibitory activity against Staphylococcus aureus DNA gyrase and topoisomerase IV.
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Mannich-Benzimidazole Derivatives as Antioxidant and Anticholinesterase Inhibitors: Synthesis, Biological Evaluations, and Molecular Docking Study ()
A series of Mannich bases of benzimidazole derivatives having a phenolic group were designed to assess their anticholinesterase and antioxidant activities. The acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities were evaluated in vitro by using Ellman's method. According to the activity results, all of the compounds exhibited moderate to good AChE inhibitory activity (except for 2a), with IC50 values ranging from 0.93 to 10.85 μM, and generally displayed moderate BuChE inhibitory activity. Also, most of the compounds were selective against BuChE. Compound 4b was the most active molecule on the AChE enzyme and also selective. In addition, we investigated the antioxidant effects of the synthesized compounds against FeCl2/ascorbic acid-induced oxidative stress in the rat brain in vitro, and the activity results showed that most of the compounds are effective as radical scavengers. Molecular docking studies and molecular dynamics simulations were also carried out. A series of Mannich bases of benzimidazole derivatives with a phenolic group were synthesized and assayed for their antioxidant activities and acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory properties. 2-[(Diethylamino)methyl]-4-(5-nitro-1H-benzo[d]imidazol-2-yl)phenol (4b) (IC50 = 0.93 µM) showed the best inhibitory activity toward AChE. Most of the compounds are almost equally active compared to tert-butyl hydroquinone as antioxidant reference.
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From Lead to Drug Utilizing a Mannich Reaction: The Topotecan Story ()
Natural products are a rich source of bioactive compounds, and numerous natural compounds have found application in cancer chemotherapy. However, unfavorable physicochemical properties often prevent the use of the original natural product as a drug. A prominent example is camptothecin from the Chinese tree Camptotheca acuminata, which shows extraordinary cytotoxic activity based on a specific molecular mode of action (inhibition of human topoisomerase I). Due to its extremely poor solubility, the original natural product cannot be used as a drug. The marketed drug topotecan was developed from this lead structure by semi-synthesis utilizing a Mannich aminomethylation as the crucial step. In this review, the long-distance run leading to this drug and further perspectives are summarized. The marketed topoisomerase I inhibitor topotecan was developed by semi-synthesis from the alkaloid camptothecin, with a Mannich aminomethylation as the central step. This review summarizes the long-distance run leading to this drug as well as further perspectives.
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Cover Picture: Arch. Pharm. Chem. Life Sci. (5/2017) ()

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Editorial Board: Arch. Pharm. Chem. Life Sci. (5/2017) ()

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Evaluation of Biological Activity and Computer-Aided Design of New Soft Glucocorticoids ()
Soft glucocorticoids are compounds that are biotransformed to inactive and non-toxic metabolites and have fewer side effects than traditional glucocorticoids. A new class of 17β-carboxamide steroids has been recently introduced by our group. In this study, local anti-inflammatory activity of these derivatives was evaluated by use of the croton oil-induced ear edema test. Glucocorticoids with the highest maximal edema inhibition (MEI) were pointed out, and the systemic side effects of those with the lowest EC50 values were significantly lower in comparison to dexamethasone. A 3D-QSAR model was created and employed for the design of 27 compounds. By use of the sequential combination of ligand-based and structure-based virtual screening, three compounds were selected from the ChEMBL library and used as a starting point for the design of 15 derivatives. Molecular docking analysis of the designed derivatives with the highest predicted MEI and relative glucocorticoid receptor binding affinity (20, 22, 24-1, 25-1, 27, VS7, VS13, and VS14) confirmed the presence of interactions with the glucocorticoid receptor that are important for the activity. Local anti-inflammatory activity and systemic side effects were evaluated for a group of novel 17β-carboxamide steroids, indicating that these compounds are potentially new soft glucocorticoids. Using 3D-QSAR analysis of these results and virtual screening of the ChEMBL library, novel derivatives were designed and eight compounds with the highest predicted local anti-inflammatory activity and relative glucocorticoid receptor binding affinity (20, 22, 24-1, 25-1, 27, VS7, VS13, and VS14) were selected.
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Benzodioxole–Pyrazole Hybrids as Anti-Inflammatory and Analgesic Agents with COX-1,2/5-LOX Inhibition and Antioxidant Potential ()
Two series of benzodioxole–pyrazole hybrids were synthesized and the IC50 values for in vitro inhibition of the enzymes cyclooxygenase 1/2 (COX-1, COX-2) and 5-lipoxygenase (5-LOX) were investigated. All compounds were tested for their in vivo anti-inflammatory and analgesic potentials using diclofenac sodium as a reference standard. Compounds 4, 11, 17, 20, 21, 26, and 27, which showed good analgesic and/or anti-inflammatory activities, were also evaluated for their ability to inhibit tumor necrosis factor (TNF)-α production, myeloperoxidase and proteinase, beside their antioxidant activity. Collectively, compounds 11, 17, and 26 displayed significant anti-inflammatory, analgesic, and antioxidant activities, beside dual COX-2 and 5-LOX inhibition. Among these, compound 26 showed high selectivity for in vitro COX-1/COX-2 inhibition, whereas the analogs 11 and 17 noticeably ameliorated the TNF-α level by 85.19 and 97.71%, respectively. A molecular docking study was performed to investigate the possible binding mode of compounds 11, 17, and 26 with the active sites of the COX-2 and 5-LOX enzymes, where they showed nearly the same binding pattern as that of celecoxib and meclofenamic acid, respectively. In two series of benzodioxole–pyrazole hybrids, compounds 11, 17, and 26 displayed significant anti-inflammatory, analgesic and antioxidant activities, beside dual cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibition. Compound 26 showed strong dual COX-2/5-LOX inhibition (IC50 = 0.33 and 3.11 µM, respectively), whereas analogs 11 and 17 noticeably ameliorated the tumor necrosis factor-α level by 85.19 and 97.71%, respectively.
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Synthesis, Anti-Inflammatory Activity, and COX-1/2 Inhibition Profile of Some Novel Non-Acidic Polysubstituted Pyrazoles and Pyrano[2,3-c]pyrazoles ()
The synthesis and evaluation of the anti-inflammatory activity of some structure hybrids comprising basically the 5-hydroxy-3-methyl-1-phenyl-4-substituted-1H-pyrazole scaffold directly linked to a variety of heterocycles and functionalities, or annulated as pyrano[2,3-c]pyrazoles, is described. According to the in vivo results and a comprehensive structure–activity relationship study, five analogs (5, 10, 17, 19, and 27) displayed remarkable anti-inflammatory profiles showing distinctive % protection and ED50 values, especially 10 and 27 (ED50 35.7 and 38.7 μmol/kg, respectively) which were nearly equiactive to celecoxib (ED50 32.1 μmol/kg). Compounds 10, 17, and 27 exhibited distinctive COX-2 inhibition with a noticeable COX-2 selectivity (SI values 7.83, 6.87, and 7.16, respectively), close to that of celecoxib (SI 8.68). Additionally, 5, 10, 17, 19, and 27 proved to be gastrointestinal tract safe (0–20% ulceration) and non-toxic, being well tolerated by the experimental animals up to 250 mg/kg orally and 80 mg/kg parenterally. Collectively, the in vivo ED50 values for the most potent five derivatives agree with their in vitro COX-2 selectivity indices, suggesting their usefulness as selective anti-inflammatory COX-2 inhibitors. The bipyrazole 10 and the pyranopyrazole 27 could be considered as the most active members in this study, being nearly equiactive to celecoxib, besides their obvious selective COX-2 inhibition, high safety margin, and predicted pharmacokinetic (ADME-T) suitability for oral use. Novel polysubstituted pyrazoles and pyranopyrazoles were synthesized and evaluated for their in vivo and in vitro anti-inflammatory activities. Five analogs (5, 10, 17, 19, and 27) displayed in vivo ED50 values that correspond to the in vitro COX-2 selectivity indices. Bipyrazole 10 and pyranopyrazole 27 (structurally related to celecoxib) showed the highest anti-inflammatory and COX-2 inhibitory activities with GIT-sparing profiles and high safety margins.
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Synthesis and Evaluation of Novel [1,2,4]Triazolo[5,1-c][1,2,4]-triazines and Pyrazolo[5,1-c][1,2,4]triazines as Potential Antidiabetic Agents ()
Inhibition of the dipeptidyl peptidase-4 (DPP4) enzyme activity and prevention of advanced glycation end (AGE) products formation represents a reliable approach to achieve control over hyperglycemia and the associated pathogenesis of diabetic vascular complications. In the frames of this research study, several triazolo- and pyrazolotriazines were synthesized and evaluated as inhibitors of AGE products formation, DPP4, glycogen phosphorylase and α-glucosidase activities, as well as AGE cross-link breakers. From the two considered classes of heterocyclic compounds, the pyrazolotriazines showed the highest potency as antiglycating agents and DPP4 inhibitors. Structure–activity relationships (SAR) for these compounds, which can be considered as potential drugs for the treatment of type 2 diabetes, were evaluated. A series of novel azolo[5,1-c][1,2,4]triazines were synthesized and evaluated as inhibitors of advanced glycation end (AGE) products formation, dipeptidyl peptidase 4, glycogen phosphorylase and α-glucosidase activities, and as AGE cross-link breakers. One of the most active compounds (16a) inhibits methylglyoxal-mediated AGE products formation with an IC50 value of 186.8 μM.
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Synthesis and Evaluation of 5-(o-Tolyl)-1H-tetrazole Derivatives as Potent Anticonvulsant Agents ()
A series of 5-(o-tolyl)-1H-tetrazole derivatives were synthesized and evaluated for their anticonvulsant activities. 1-(2-Methylbenzyl)-5-(o-tolyl)-1H-tetrazole (3h) showed important anticonvulsant activity against the MES-induced seizures, as well as lower neurotoxicity with an ED50 value of 12.7 mg/kg and a TD50 value of over 500 mg/kg after intraperitoneal injection into mice, providing 3h with a high protective index (TD50/ED50) of over 39.4. The achieved results prove that the distinctive compounds could be valuable as a model for future development, adaptation, and investigation to construct more active analogues. In a series of 5-(o-tolyl)-1H-tetrazole derivatives, 1-(2-methylbenzyl)-5-(o-tolyl)-1H-tetrazole (3h) showed significant anticonvulsant activity against MES-induced seizures and lower neurotoxicity after intraperitoneal injection into mice, providing 3h with a high protective index (TD50/ED50) of over 39.4. Some compounds could be valuable as a model to construct more active analogues.
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Synthesis and Structure–Activity Relationships of Novel Benzylamine-Type Antifungals as Butenafine-Related Antimycotics ()
Benzylamine-type antimycotics like naftifine, butenafine, or terbinafine are a well-known class of antimycotics since the 1980s. The following paper describes the synthesis and biological evaluation of a series of novel benzylamine-type antimycotics characterized by an isooctyl side chain and various substituents at the benzylamine moiety. The compounds were prepared from benzaldehyde derivatives and 2-amino-6-methylheptane by reductive amination with sodium triacetoxyborohydride and subsequent precipitation with hydrogen chloride. The antimycotic activity of the resulting compounds was evaluated in an agar diffusion assay against the yeasts C. glabrata and Yarrowia lipolytica, the mold Aspergillus niger and the dermatophyte H. burtonii. The compounds were also tested in a microdilution assay against the yeast Candida glabrata and the dermatophyte H. burtonii to determine the minimal inhibitory concentrations (MIC). Compounds with an aromatic ether side chain or a short alkyl ether side chain showed significant antimycotic activity against C. glabrata, comparable to terbinafine or clotrimazole. A series of novel benzylamine-type antimycotics characterized by an isooctyl side chain and various substituents at the benzylamine moiety were synthesized and evaluated for their biological activities. Compounds with an aromatic ether side chain or a short alkyl ether side chain showed significant antimycotic activity against Candida glabrata, comparable to terbinafine or clotrimazole.
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Diclofenac-Based Hydrazones and Spirothiazolidinones: Synthesis, Characterization, and Antimicrobial Properties ()
We report here the synthesis, structural characterization, and biological evaluation of novel diclofenac-based hydrazone (4a–f) and spirothiazolidinone (5a–f, 6a–f) derivatives designed as potential antimicrobial agents. The compounds were evaluated in vitro for their antiviral activity against a wide spectrum of DNA and RNA viruses. They were further screened in vitro against different strains of bacteria and fungi. The hydrazone derivatives, 4a and 4c–f, were found to be active against herpesviruses (HSV-1, HSV-2, and HSV-1 TK−), vaccinia virus, and Coxsackie B4 virus, with EC50 values between 6.6 µg/mL and 14.7 μg/mL, and the selectivity index values were greater than 10 for 4a and 4f. The newly synthesized compounds (4–6) were inactive against the bacterial and the fungal strains tested, at levels below 2500, 1250, or 625 μg/mL. Interestingly, the key intermediate 3 with a free hydrazide moiety displayed antifungal properties against Candida albicans and C. parapsilosis at MIC values of 4.88 µg/mL and 78.12 μg/mL, respectively. A new series of diclofenac-based hydrazones (4a–f) and spirothiazolidinones (5a–f, 6a–f) were synthesized and assayed for antimicrobial activity against a wide spectrum of viral, bacterial, and fungal pathogens. The hydrazone derivatives, 4a and 4c–f, were found to be active against herpesviruses (HSV-1, HSV-2, and HSV-1 TK–), vaccinia virus, and Coxsackie B4 virus, with EC50 values between 6.6 µg/mL and 14.7 µg/mL, and the selectivity index values were greater than 10 for 4a and 4f.
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Synthesis, Characterization, and Biological Evaluation of Some Novel Quinoxaline Derivatives as Antiviral Agents ()
Ethyl (6,7-dimethyl-2-oxo-3,4-dihydroquinoxalin-3-yl)acetate and ethyl (6-methyl-2-oxo-3,4-dihydroquinoxalin-3-yl)acetate (1a,b), 3-methylquinoxalin-2(1H)-one (4) and 1,4-dihydroquinoxaline-2,3-dione (11) were the starting precursors for nine novel quinoxaline compounds, 3a, 6, 10, 13, 15, 16, 17, 18, and 20, via adopting different nucleophilic reactions. The synthesized compounds were tested for their antiviral activity against HCV, HBV, HSV-1, and HCMV. Concomitantly, their safety profile was investigated as well as their selectivity against the viral strains. The Virology Unit at the University of Alabama recorded that two compounds, i.e., 1a and 20, exhibited highly potent activity against HCMV with lower IC50 values (<0.05 μM) compared to ganciclovir (IC50 = 0.59 μM). Compounds 1a and 20 also exhibited low cytotoxicity together with a high selectivity index. A four-step preparation method comprising hydrazinolysis, reaction with triethylorthoformate, nucleophilic attack of 2-aminopyridine on hydrazonoderivatives, then intramolecular cyclization was applied to transform compound 1a to 20. The quinoxaline derivative 20 exhibited higher activity against human cytomegalovirus (EC50 < 0.05 µM) compared to ganciclovir as the reference standard (EC50 = 0.59 µM).
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