Archiv der Pharmazie

An Efficient Synthesis of bi-Aryl Pyrimidine Heterocycles: Potential New Drug Candidates to Treat Alzheimer's Disease ()
A series of 13 novel pyrimidine-based sulfonamides 6a–m were synthesized in short periods of time under microwave conditions in good to excellent yield (54–86%). The chemical structures of these heterocycles consist of a central pyrimidine ring having a phenyl group and pyrimidine groups with sulfonamide motifs. The enzyme inhibitory potential of these compounds was investigated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) because these enzymes play a crucial role in the treatment of Alzheimer's disease. As compared to the reference compound eserine (IC50 = 0.04 ± 0.0001 μM for AChE and IC50 = 0.85 ± 0.0001 μM for BChE), the IC50 values of the synthesized compounds ranged from 3.73 ± 0.61 μM to 57.36 ± 0.22 μM for AChE and 4.81 ± 0.16 μM to 111.61 ± 0.53 μM for BChE. Among these tested compounds, 6j having a −CH3 group was found to be the most potent one against both enzymes (AChE, IC50 = 3.73 ± 0.61 μM; BChE, IC50 = 4.81 ± 0.16 μM). Quantitative structure–activity relationship (QSAR) and molecular docking studies of the synthesized compounds were also performed. A series of 13 novel pyrimidine-based sulfonamides were synthesized under microwave conditions in good to excellent yield (54–86%). The acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory potential of these compounds was investigated. Compound 6j having a –CH3 group was found to be the most potent one against both enzymes (AChE, IC50 = 3.73 ± 0.61 µM; BChE, IC50 = 4.81 ± 0.16 µM).
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Interaction of Approved Drugs with Synaptic Vesicle Protein 2A ()
Levetiracetam (LEV) and its recently approved derivative brivaracetam are anti-epileptic drugs with a unique mechanism of action. The synaptic vesicle protein 2A (SV2A) was previously identified as their main target. In the current study, we tested a collection of 500 approved drugs for interaction with the human SV2A protein expressed in Chinese hamster ovary cells. Competition binding studies were performed using cell lysates with high SV2A expression and [3H]brivaracetam as a radioligand. A hit rate of 3% was obtained, defined as compounds that inhibited radioligand binding by more than 90% at a screening concentration of 20 μM. Subsequent concentration–inhibition curves revealed the antihistaminic prodrug loratadine (Ki = 1.16 μM) and the antimalarial drug quinine (Ki = 2.03 μM) to be the most potent SV2A protein ligands of the investigated drug library. Both compounds were similarly potent as LEV (Ki = 1.74 μM), providing structurally novel scaffolds for SV2A ligands. A pharmacophore model was established, which indicated steric and electronic conformities of brivaracetam with the new SV2A ligands, and preliminary structure–activity relationships were determined. The anti-convulsive effects of the natural product quinine may – at least in part – be explained by interaction with SV2A. Loratadine and quinine represent new lead structures for anti-epileptic drug development. [3H]Brivaracetam binding to human synaptic vesicle protein 2A (SV2A), the target of the anti-epileptic drug levetiracetam (LEV), was used to screen a library of approved drugs. Loratadine (Ki = 1.16 µM) and quinine (Ki = 2.03 µM) were found to have similar potency as LEV (Ki = 1.74 µM). Pharmacophore modeling revealed common features of the three drugs. Interaction of quinine with SV2A may be responsible for its anti-convulsive effects.
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Design, Synthesis, and Biological Evaluation of Novel 1,2,4-Trioxanes as Potential Antimalarial Agents ()
A series of substituted 1,2,4-trioxanes were synthesized and evaluated for their antimalarial potential, in silico ADME properties and cytotoxicity on neuronal cell lines. Among the 15 synthesized substituted 1,2,4-trioxanes, two compounds (compound 15, IC50 = 25.71 nM; compound 21, IC50 = 19.6 nM) exhibited promising in vitro antimalarial potential comparable to those of the existing drugs chloroquine and artemisinin. Both of these compounds were found to be nontoxic up to 20 µM concentration in neuronal PC-12 cells. Compound 21 may serve as an optimized lead compound because of its less in vitro toxicity and lower probability to cross the blood brain barrier. A series of substituted 1,2,4-trioxanes were synthesized and evaluated for their antimalarial potential, ADME properties, and neuronal cell cytotoxicity. Two compounds (15, IC50 = 25.71 nM; 21, IC50 = 19.6 nM) showed in vitro antimalarial potential comparable to those of chloroquine and artemisinin. Due to its less toxicity and low probability to cross the blood brain barrier, compound 21 can be considered an optimized lead.
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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. (2/2017) ()

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Editorial Board: Arch. Pharm. Chem. Life Sci. (2/2017) ()

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Design and Synthesis of Novel 4-Phenoxyquinolines Bearing 3-Hydrosulfonylacrylamido or 1H-Imidazole-4-carboxamido Scaffolds as c-Met Kinase Inhibitors ()
A series of novel 6,7-disubstituted-4-phenoxyquinoline derivatives bearing (E)-3-hydrosulfonylacrylamido or 1H-imidazole-4-carboxamido moieties were designed, synthesized and evaluated for their cytotoxicity against A549, MKN-45, and HT-29 cancer cell lines in vitro. All the target compounds showed moderate to significant cytotoxic activity against the tested cells with IC50 values ranging from 0.13 to 2.65 µM. Five of them were further examined for their inhibitory activity against c-Met kinase, which identified compound 30 as a promising agent (c-Met IC50 = 1.52 nM) with IC50 values of 0.24, 0.45, and 0.13 µM against HT-29, MKN-45, and A549 cells, respectively. A series of novel 6,7-disubstituted-4-phenoxyquinoline derivatives bearing (E)-3-hydrosulfonylacrylamido or 1H-imidazole-4-carboxamido moieties were designed, synthesized and evaluated for their cytotoxicity and c-Met kinase activity in vitro. Compound 30 was identified as a lead compound for further structural optimization and antitumor activity screening purposes.
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New 3-Substituted-2-(4-hydroxyanilino)pyridine Derivatives: Synthesis, Antitumor Activity, and Tubulin Polymerization Inhibition ()
A series of new pyridine derivatives 4a–c, 5a–d, 6a–d, 7a–f, and 8a–f structurally related to ABT-751 were synthesized and characterized by spectroscopic means and elemental analysis. All the synthesized compounds were tested for their cytotoxic activity in vitro against the HCT-116 and HepG-2 cancer cell lines using the MTT assay. The results showed that compound 8d has higher cytotoxic activity than the reference antimitotic agent colchicine, against both tested cell lines, with IC50 = 0.52 and 1.40 μM, respectively. The three most active compounds, 5d, 8b, and 8d, were further screened in vitro for inhibition of tubulin and showed remarkable results in comparison to colchicine. 4-{3-[5-(4-Methoxyphenylamino)-1,3,4-oxadiazol-2-yl]-pyridin-2- ylamino}phenol (8d) was designed based on the potent cytotoxic and tubulin inhibitory activities displayed by ABT-751 and IMC-038525. Compound 8d exhibited potent cytotoxic activity against HCT- 116 and HepG-2 cells with IC50 values of 0.52 and 1.40 µM, respectively. It also displayed considerable tubulin inhibitory activity: 92.60 and 93.20% against HCT-116 and HepG-2 cells, respectively.
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Design, Synthesis, and Biological Evaluation of Novel Quinazoline Clubbed Thiazoline Derivatives ()
A novel series of quinazoline clubbed thiazoline derivatives was rationally designed and synthesized. The newly synthesized compounds were evaluated for in vitro dipeptidyl peptidase IV (DPP-4) inhibitory activity. Compounds that showed good to moderate activity were compared using linagliptin as standard. Compound 4x (IC50 = 1.12 nM) exhibited the most promising results. The special chemical feature of compound 4x also imparts good inhibition selectivity for DPP-4 over DPP-8/9. Moreover, docking of compound 4x into the active site of DPP-4 illustrates its possible binding interactions. A novel series of quinazoline clubbed thiazoline derivatives was rationally designed, synthesized and evaluated for their in vitro dipeptidyl peptidase IV (DPP-4) inhibitory activity, compared to the standard linagliptin. Docking of the most promising compound (4x) into the active site of DPP-4 reveals its possible binding interactions.
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Synthesis of Novel Pyrazolines, Their Boron–Fluorine Complexes, and Investigation of Antibacterial, Antioxidant, and Enzyme Inhibition Activities ()
New 3,5-disubstituted-2-pyrazoline derivatives (4–6), their boron-fluorine complexes (boron (3-(2′-aminophenyl),5-(2′-/3′-/4′-pyridyl)pyrazoline, BOAPPY) (7–9) and boron 1,2′-diazaflavone complex (BODAF) (11) were synthesized starting from azachalcones (1–3) to diazaflavone (10), respectively. Biological evaluation of compounds 4–9 and 11 showed remarkable antioxidant, antibacterial, and acetylcholinesterase and tyrosinase enzyme inhibition activities. All newly synthesized compounds 4–9 and 11 showed respectable antibacterial effect with minimum inhibitory concentrations in the range of 4.7–150 μg/mL. New 3,5-disubstituted-2-pyrazoline derivatives (4–6), their boron-fluorine complexes (BOAPPY) (7–9) and boron 1,2′-diazaflavone complex (BODAF) (11) were synthesized starting from azachalcones to diazaflavone, respectively. Compounds 4–9 and 11 showed remarkable antioxidant, antibacterial, acetylcholinesterase-inhibitory, and tyrosinase-inhibitory activities, as well as good antibacterial effects.
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Design and Synthesis of 5-Substituted Benzo[d][1,3]dioxole Derivatives as Potent Anticonvulsant Agents ()
A series of 5-substituted benzo[d][1,3]dioxole derivatives was designed, synthesized, and tested for anticonvulsant activity using the maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) screens. Neurotoxicity was determined by rotarod test. In the preliminary screening, six compounds, 3a, 3c, 3d, and 4d–f, showed promising anticonvulsant activities in the MES model, and compounds 4c and 4d exhibited full protection against seizures at doses of 300 mg/kg in the scPTZ model. Among the synthesized compounds, 3c as the most active compound showed high protection against the MES-induced seizures with an ED50 value of 9.8 mg/kg and a TD50 value of 229.4 mg/kg after intraperitoneal injection into mice, thus providing compound 3c with a high protective index (TD50/ED50) of 23.4 comparable to those of reference antiepileptic drugs. A series of 5-substituted benzo[d][1,3]dioxole derivatives was designed, synthesized, and tested for anticonvulsant activity and neurotoxicity. The most active compound 3c showed high protection against MES-induced seizures, with an ED50 value of 9.8 mg/kg and a TD50 value of 229.4 mg/kg after intraperitoneal injection into mice. The protective index of compound 3c (TD50/ED50 = 23.4) is comparable to those of reference antiepileptic drugs.
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Synthesis, Anticonvulsant Activity, and SAR Study of Novel 4-Quinazolinone Derivatives ()
Series of N-(4-substitutedphenyl)-4-(1-methyl (or 1,2-dimethyl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)-alkanamides (5a–j) and 4-chloro-N′-((1-methyl (or 1,2-dimethyl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)-alkaloyl)benzohydrazides (6a–f) were designed based on the previously reported essential structural features for anticonvulsant activity. Several amino acids were incorporated within the synthesized quinazolin-4(3H)-ones to improve their bioavailability and the anticonvulsant activity. Synthesis of the target compounds was accomplished in four steps starting from the reaction between N-methyl isatoic anhydride and the appropriate amino acid. Then, the carboxylic acid group was utilized to synthesize the required final structures. The new quinazolinone derivatives were evaluated for their anticonvulsant activity according to the Anticonvulsant Drug Development (ADD) Program protocol. All the 16 new quinazolinones exhibited good anticonvulsant activity; especially 5f, 5b, and 5c showed superior anticonvulsant activities in comparison to the reference drug, with ED50 values of 28.90, 47.38, and 56.40 mg/kg, respectively. A series of N-(4-substitutedphenyl)-4-(1-methyl (or 1,2-dimethyl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)alkanamides (5a–j) and 4-chloro-N′-((1-methyl (or 1,2-dimethyl)-4-oxo-1,2-dihydroquinazolin-3(4H)-yl)alkaloyl)benzohydrazides (6a–f) were designed, synthesized and evaluated for their anticonvulsant activity using both the MES and scPTZ screens. All compounds showed good anticonvulsant activity with minimum levels of neurotoxicity.
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2-Benzamido-4-methylthiazole-5-carboxylic Acid Derivatives as Potential Xanthine Oxidase Inhibitors and Free Radical Scavengers ()
The new chemical entities febuxostat and topiroxostat have been approved by the US Food and Drug Administration, opening new avenues for exploiting different heterocycles other than purines as xanthine oxidase (XO) inhibitors. A different series of substituted 2-benzamido-4-methylthiazole-5-carboxylic acid derivatives (5a–r) was synthesized and characterized by the collective use of IR, 1H and 13C NMR, and mass spectroscopy, for the treatment of gout and hyperuricemia. In vitro studies of the synthesized derivatives revealed that the presence of a fluoro group at the para position in 5b (IC50 = 0.57 μm) and a chloro group in 5c (IC50 = 0.91 μm) signifies excellent XO inhibitory activity among the series, along with their DPPH free radial scavenging activity. In vivo serum uric acid inhibition studies established that 5b and 5c displayed 62 and 53% uric acid inhibition, respectively. Studies on enzyme kinetics indicated that 5b acts as a mixed type inhibitor. In silico prediction by various softwares also helped in the recognition of potent XO inhibitors. A series of 2-benzamido-4-methylthiazole-5-carboxylic acid derivatives as structural analogs of febuxostat was synthesized and their xanthine oxidase inhibitory activities were established by in vitro and in vivo methods. Compound 5b exhibited significant uric acid inhibition activity along with DPPH free radical scavenging activity.
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