Archiv der Pharmazie

Isophthalic Acid-Based HDAC Inhibitors as Potent Inhibitors of HDAC8 from Schistosoma mansoni ()
Schistosoma mansoni histone deacetylase 8 (SmHDAC8) has been recently identified as a new potential target for the treatment of schistosomiasis. A series of newly designed and synthesized alkoxyamide-based and hydrazide-based HDAC inhibitors were tested for inhibitory activity against SmHDAC8 and human HDACs 1, 6, and 8. The front runner compounds showed submicromolar activity against SmHDAC8 and modest preference for SmHDAC8 over its human orthologue hHDAC8. Docking studies provided insights into the putative binding mode in SmHDAC8 and allowed rationalization of the observed selectivity profile. A series of newly designed and synthesized alkoxyamide-based and hydrazide-based histone deacetylase (HDAC) inhibitors were tested for inhibitory activity against Schistosoma mansoni HDAC8 and human HDACs 1, 6, and 8. Docking studies provide insights into the putative binding mode in SmHDAC8 and allow rationalization of the observed selectivity profile.
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Design, Synthesis, and Biological Evaluation of Isothiosemicarbazones with Antimycobacterial Activity ()
A series of benzaldehyde and salicylaldehyde-S-benzylisothiosemicarbazones was synthesized and tested against 12 different strains of mycobacteria, Gram-positive and Gram-negative bacteria, and the significant selectivity toward mycobacteria was proved. Twenty-eight derivatives were evaluated for the inhibition of isocitrate lyase, which is a key enzyme of the glyoxylate cycle necessary for latent tuberculosis infection, and their iron-chelating properties were investigated. Two derivatives, 5-bromosalicylaldehyde-S-(4-fluorobenzyl)-isothiosemicarbazone and salicylaldehyde-S-(4-bromobenzyl)-isothiosemicarbazone, influenced the isocitrate lyase activity and caused a better inhibition at 10 μmol/L than 3-nitropropionic acid, a standard inhibitor. The compounds were also found to act as exogenous chelators of iron, which is an obligate cofactor for many mycobacterial enzymes. Due to their low cytotoxicity, together with the activity against isocitrate lyase and the ability to sequester iron ions, the compounds belong to potential antibiotics with the main effect on mycobacteria. A series of benzaldehyde and salicylaldehyde-S-benzylisothiosemicarbazones was synthesized and tested for antimycobacterial selectivity. Twenty-eight derivatives were evaluated for the inhibition of isocitrate lyase, a key enzyme of the glyoxylate cycle necessary for latent tuberculosis infection. The compounds show promising activity as potential antibiotics with the main effect on mycobacteria.
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Design, Synthesis, and Evaluation of Novel Tyrosine-Based DNA Gyrase B Inhibitors ()
The discovery and synthesis of new tyrosine-based inhibitors of DNA gyrase B (GyrB), which target its ATPase subunit, is reported. Twenty-four compounds were synthesized and evaluated for activity against DNA gyrase and DNA topoisomerase IV. The antibacterial properties of selected GyrB inhibitors were demonstrated by their activity against Staphylococcus aureus and Enterococcus faecalis in the low micromolar range. The most promising compounds, 8a and 13e, inhibited Escherichia coli and S. aureus GyrB with IC50 values of 40 and 30 µM. The same compound also inhibited the growth of S. aureus and E. faecalis with minimal inhibitory concentrations (MIC90) of 14 and 28 µg/mL, respectively. A series of novel tyrosine-based inhibitors of DNA gyrase B (GyrB) were designed, synthesized, and evaluated against DNA gyrase and DNA topoisomerase IV. Compounds 8a and 13e, which inhibited E. coli and S. aureus GyrB and displayed inhibitory activity against the growth of S. aureus and E. faecalis were identified as promising compounds for further structural optimization.
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Synthesis and Antiproliferative Activity of Thioxoflavones Mannich Base Derivatives ()
Two series of 12 novel thioxoflavones Mannich base derivatives 5a–f and 6a–f were synthesized via Mannich reaction of 4′,7-dimethoxy-5-hydroxyflavothione (3) or 3′,4′,7-trimethoxy-5-hydroxyflavothione (4) with appropriate aliphatic amines or alicyclic amines and formaldehyde. Thioxoflavones 3 and 4 were prepared from 4′,7-dimethoxy-5-hydroxyflavone (1) and 3′,4′,7-trimethoxy-5-hydroxyflavone (2) with Lawesson's reagent, respectively. Their antiproliferative activities in vitro were evaluated on a panel of three human cell lines (HeLa, HCC1954, and SK-OV-3) by CCK-8 assay. The results showed that most of the thioxoflavones and their Mannich base derivatives exhibited potential antiproliferative activities on the tested cancer cell lines, with IC50 values ranging from 9.16 to 55.50 μM. In particular, thioxoflavone 4 and the thioxoflavone Mannich base derivatives 5a and 5d showed the best antiproliferative activity on all three human cancer cell lines; they are promising candidates worthy of further development. The structures of all synthesized compounds were confirmed by 1H NMR, 13C NMR, IR, and MS techniques. Two series of thioxoflavones Mannich base derivatives, 5a–f and 6a–f, were synthesized and their antiproliferative activities were evaluated in vitro on a panel of three human cancer cell lines (HeLa, HCC1954, and SK-OV-3). Thioxoflavone 4 and the thioxoflavone Mannich base derivatives 5a and 5d, which showed the best antiproliferative activity on all three tested cell lines, are promising candidates for further development.
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Synthesis and Biological Evaluation of New Diarylpyrazole and Triarylimidazoline Derivatives as Selective COX-2 Inhibitors ()
New series of diarylpyrazoles 8a–f and triarylimidazoline-5-ones 11a–g were synthesized and evaluated for their in vitro cyclooxygenase-1 (COX-1) and COX-2 inhibitory activity and in vivo anti-inflammatory activity. The synthesized compounds showed good selectivity for COX-2; compounds 8a, 8d, 8f, 11a, and 11c exhibited the highest COX-2 selectivity indexes (SI = 4.77–5.43) compared to the reference drug celecoxib (SI = 7.8). All compounds showed good in vivo anti-inflammatory activity, especially compounds 8a, 8f, 11c, and 11d, which also showed some similarities to the time interval pattern of celecoxib at all different time intervals (1, 3, and 6 h). New series of diarylpyrazoles (8a–f) and triarylimidazoline-5-ones (11a–g) were synthesized and evaluated for their in vitro cyclooxygenase-1/2 (COX-1/2)-inhibitory and in vivo anti-inflammatory activities. Compounds 8a, 8d, 8f, 11a, and 11c exhibited the highest COX-2 selectivity (SI = 4.77–5.43) compared to celecoxib (SI = 7.8) and all compounds showed good in vivo anti-inflammatory activity.
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Design and Synthesis of 1,2,4-Triazolo[3,2-b]-1,3,5-thiadiazine Derivatives as a Novel Template for Analgesic/Anti-Inflammatory Activity ()
Previously, we demonstrated that certain heterocyclic compounds derived from 3-substituted-1,2,4-triazole-5-thiones had promising analgesic/anti-inflammatory activities together with low ulcerogenic properties. Therefore, we sought to design and synthesize new derivatives of triazol-5-thiones-fused heterocycles. In the present study, a series of novel bis-Mannich bases, namely 2,6-disubstituted-6,7-dihydro-5H-1,2,4-triazolo[3,2-b]-1,3,5-thiadiazines (1a–d, 2a–c, and 3a–d), were synthesized and characterized to assess their possible anti-inflammatory/analgesic properties. Additionally, their ability to induce gastric toxicity was also evaluated. Several of the condensed compounds produced a degree of analgesic activity comparable to reference drugs in both the hot plate and tail-flick tests. A strong anti-inflammatory effect was observed for the derivatives carrying a benzyl group at the second position (2a–c). The majority of the prepared compounds caused comparatively less gastrointestinal (GI) side effects than the reference drugs naproxen and indomethacin did. These results showed that 1,2,4-triazolo[3,2-b]-1,3,5-thiadiazine derivatives might afford a safer alternative to currently available analgesic/anti-inflammatory agents for the treatment and management of inflammatory disease and pain. Several of the new compounds derived from 1,2,4-triazolo[3,2-b]-1,3,5-thiadiazine had marked analgesic activity with comparatively less gastrointestinal side effects. A strong anti-inflammatory effect was observed for the derivatives carrying a benzyl group at the second position. Thus, 1,2,4-triazolo[3,2-b]-1,3,5-thiadiazine derivatives might afford a safer alternative to the currently available analgesic/anti-inflammatory agents.
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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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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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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. (6/2017) ()

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Editorial Board: Arch. Pharm. Chem. Life Sci. (6/2017) ()

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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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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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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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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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