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30 pages, 13320 KiB

Open AccessReview

Structural Aspects of Arylpiperazines as Aminergic GPCR Ligands

by Agata Bartyzel, Beata Cristóvão and Agnieszka A. Kaczor

Molecules 2025, 30(12), 2545; https://doi.org/10.3390/molecules30122545 - 11 Jun 2025

Viewed by 1228

Arylpiperazines are considered a “privileged scaffold” in medical chemistry due to their versatility and modular structure, enabling modifications towards diverse molecular targets with desired potency, selectivity, and pharmacokinetic properties. In particular, arylpiperazines are aminergic G protein-coupled receptor (GPCR) ligands and neurotransmitter transporter inhibitors, making this group of compounds attractive in central nervous system (CNS) drug discovery for treating schizophrenia, depression, sleep disorders, and Parkinson’s disease (PD). Furthermore, arylpiperazines may possess anticancer properties and can modulate some molecular targets involved in this disease. This review focuses on the structural aspects of arylpiperazines as aminergic GPCR ligands. The review centers on biologically active arylpiperazines with known X-ray structures, providing a detailed discussion of the conformations in the solid state. Next, their interactions with the aminergic GPCRs, based on experimental and molecular modelling studies, are addressed, making this review a comprehensive resource for medicinal and structural chemists working on arylpiperazines. Full article

(This article belongs to the Special Issue Design, Synthesis, and Analysis of Potential Drugs, 3rd Edition)

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22 pages, 4477 KiB

Open AccessArticle

Design and Synthesis of a Novel 4-aryl-N-(2-alkoxythieno [2,3-b]pyrazine-3-yl)-4-arylpiperazine-1-carboxamide DGG200064 Showed Therapeutic Effect on Colon Cancer through G2/M Arrest

by Eun-Sil Lee, Nayeon Kim, Joon Hee Kang, Aizhan Abdildinova, Seon-Hyeong Lee, Myung Hwi Lee, Nam Sook Kang, Tae-Sung Koo, Soo-Youl Kim and Young-Dae Gong

Pharmaceuticals 2022, 15(5), 502; https://doi.org/10.3390/ph15050502 - 20 Apr 2022

Cited by 5 | Viewed by 3440

Abstract

Cancer cells are characterized by an abnormal cell cycle. Therefore, the cell cycle has been a potential target for cancer therapeutic agents. We developed a new lead compound, DGG200064 (7c) with a 2-alkoxythieno [2,3-b]pyrazine-3-yl)-4-arylpiperazine-1-carboxamide core skeleton. To evaluate its properties, compound DGG200064 was tested in vivo through a xenograft mouse model of colorectal cancer using HCT116 cells. The in vivo results showed high cell growth inhibition efficacy. Our results confirmed that the newly synthesized DGG200064 inhibits the growth of colorectal cancer cells by inducing G2/M arrest. Unlike the known cell cycle inhibitors, DGG200064 (GI₅₀ = 12 nM in an HCT116 cell-based assay) induced G2/M arrest by selectively inhibiting the interaction of FBXW7 and c-Jun proteins. Additionally, the physicochemical properties of the lead compounds were analyzed. Based on the results of the study, we suggested further development of DGG200064 as a novel oral anti-colorectal cancer drug. Full article

(This article belongs to the Topic Compounds with Medicinal Value)

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10 pages, 2339 KiB

Open AccessCommunication

Design, Synthesis and 5-HT_1A Binding Affinity of N-(3-(4-(2-Methoxyphenyl)piperazin-1-yl)propyl)tricyclo[3.3.1.1^3,7]decan-1-amine and N-(3-(4-(2-Methoxyphenyl)piperazin-1-yl)propyl)-3,5-dimethyl-tricylo[3.3.1.1^3,7]decan-1-amine

by Grigoris Zoidis, María Isabel Loza and Marco Catto

Molbank 2022, 2022(1), M1353; https://doi.org/10.3390/M1353 - 10 Mar 2022

Cited by 1 | Viewed by 2910

Abstract

Based on previously highlighted structural features, the development of highly selective 5-HT_1A receptor inhibitors is closely linked to the incorporation of a 4-alkyl-1-arylpiperazine scaffold on them. In this paper, we present the synthesis of two new compounds bearing the 2-MeO-Ph-piperazine moiety linked via a three carbon atom linker to the amine group of 1-adamantanamine and memantine, respectively. Both were tested for their binding affinity against 5-HT_1A receptor. N-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)tricyclo[3.3.1.1^3,7]decan-1-amine fumarate (8) and N-(3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)-3,5-dimethyl-tricylo[3.3.1.1^3,7]decan-1-amine fumarate (10) proved to be highly selective ligands towards 5-HT_1A receptor with a binding constant of 1.2 nM and 21.3 nM, respectively, while 5-carboxamidotriptamine (5-CT) (2) was used as an internal standard for this assay with a measured K_i = 0.5 nM. Full article

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21 pages, 3906 KiB

Open AccessArticle

In Vitro and In Silico Evaluation of New 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]pyridazinone as Promising Cyclooxygenase Inhibitors

by Krzysztof Peregrym, Łukasz Szczukowski, Benita Wiatrak, Katarzyna Potyrak, Żaneta Czyżnikowska and Piotr Świątek

Int. J. Mol. Sci. 2021, 22(17), 9130; https://doi.org/10.3390/ijms22179130 - 24 Aug 2021

Cited by 18 | Viewed by 3517

Abstract

Since long-term use of classic NSAIDs can cause severe side effects related mainly to the gastroduodenal tract, discovery of novel cyclooxygenase inhibitors with a safe gastric profile still remains a crucial challenge. Based on the most recent literature data and previous own studies, we decided to modify the structure of already reported 1,3,4-oxadiazole based derivatives of pyrrolo[3,4-d]pyridazinone in order to obtain effective COX inhibitors. Herein we present the synthesis, biological evaluation and molecular docking studies of 12 novel compounds with disubstituted arylpiperazine pharmacophore linked in a different way with 1,3,4-oxadiazole ring. None of the obtained molecules show cytotoxicity on NHDF and THP-1 cell lines and, therefore, all were qualified for further investigation. In vitro cyclooxygenase inhibition assay revealed almost equal activity of new derivatives towards both COX-1 and COX-2 isoenzymes. Moreover, all compounds inhibit COX-2 isoform better than Meloxicam which was used as reference. Anti-inflammatory activity was confirmed in biological assays according to which title molecules are able to reduce induced inflammation within cells. Molecular docking studies were performed to describe the binding mode of new structures to cyclooxygenase. Investigated derivatives take place in the active site of COX, very similar to Meloxicam. For some compounds, promising druglikeness was calculated using in silico predictions. Full article

(This article belongs to the Special Issue Bioactive Oxadiazoles 2.0)

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22 pages, 3128 KiB

Open AccessArticle

New 1,3,4-Oxadiazole Derivatives of Pyridothiazine-1,1-Dioxide with Anti-Inflammatory Activity

by Teresa Glomb, Benita Wiatrak, Katarzyna Gębczak, Tomasz Gębarowski, Dorota Bodetko, Żaneta Czyżnikowska and Piotr Świątek

Int. J. Mol. Sci. 2020, 21(23), 9122; https://doi.org/10.3390/ijms21239122 - 30 Nov 2020

Cited by 33 | Viewed by 4384

Abstract

Numerous studies have confirmed the coexistence of oxidative stress and inflammatory processes. Long-term inflammation and oxidative stress may significantly affect the initiation of the neoplastic transformation process. Here, we describe the synthesis of a new series of Mannich base-type hybrid compounds containing an arylpiperazine residue, 1,3,4-oxadiazole ring, and pyridothiazine-1,1-dioxide core. The synthesis was carried out with the hope that the hybridization of different pharmacophoric molecules would result in a synergistic effect on their anti-inflammatory activity, especially the ability to inhibit cyclooxygenase. The obtained compounds were investigated in terms of their potencies to inhibit cyclooxygenase COX-1 and COX-2 enzymes with the use of the colorimetric inhibitor screening assay. Their antioxidant and cytotoxic effect on normal human dermal fibroblasts (NHDF) was also studied. Strong COX-2 inhibitory activity was observed after the use of TG6 and, especially, TG4. The TG11 compound, as well as reference meloxicam, turned out to be a preferential COX-2 inhibitor. TG12 was, in turn, a non-selective COX inhibitor. A molecular docking study was performed to understand the binding interaction of compounds at the active site of cyclooxygenases. Full article

(This article belongs to the Special Issue Bioactive Oxadiazoles)

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28 pages, 2976 KiB

Open AccessArticle

L-Arginine/Nitric Oxide Pathway Is Altered in Colorectal Cancer and Can Be Modulated by Novel Derivatives from Oxicam Class of Non-Steroidal Anti-Inflammatory Drugs

by Małgorzata Krzystek-Korpacka, Berenika Szczęśniak-Sięga, Izabela Szczuka, Paulina Fortuna, Marek Zawadzki, Agnieszka Kubiak, Magdalena Mierzchała-Pasierb, Mariusz G. Fleszar, Łukasz Lewandowski, Paweł Serek, Natalia Jamrozik, Katarzyna Neubauer, Jerzy Wiśniewski, Radosław Kempiński, Wojciech Witkiewicz and Iwona Bednarz-Misa

Cancers 2020, 12(9), 2594; https://doi.org/10.3390/cancers12092594 - 11 Sep 2020

Cited by 23 | Viewed by 5979

Abstract

L-arginine/nitric oxide pathway metabolites are altered in colorectal cancer (CRC). We evaluated underlying changes in pathway enzymes in 55 paired tumor/tumor-adjacent samples and 20 normal mucosa using quantitative-PCR and assessed the impact of classic and novel oxicam analogues on enzyme expression and intracellular metabolite concentration (LC-MS/MS) in Caco-2, HCT116, and HT-29 cells. Compared to normal mucosa, ARG1, PRMT1, and PRMT5 were overexpressed in both tumor and tumor-adjacent tissue and DDAH2 solely in tumor-adjacent tissue. Tumor-adjacent tissue had higher expression of ARG1, DDAH1, and DDAH2 and lower NOS2 than patients-matched tumors. The ARG1 expression in tumors increased along with tumor grade and reflected lymph node involvement. Novel oxicam analogues with arylpiperazine moiety at the thiazine ring were more effective in downregulating DDAHs and PRMTs and upregulating ARG2 than piroxicam and meloxicam. An analogue distinguished by propylene linker between thiazine’s and piperazine’s nitrogen atoms and containing two fluorine substituents was the strongest inhibitor of DDAHs and PRMTs expression, while an analogue containing propylene linker but no fluorine substituents was the strongest inhibitor of ARG2 expression. Metabolic reprogramming in CRC includes overexpression of DDAHs and PRMTs in addition to ARG1 and NOS2 and is not restricted to tumor tissue but can be modulated by novel oxicam analogues. Full article

(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)

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14 pages, 1892 KiB

Open AccessArticle

Novel 8-Substituted Coumarins That Selectively Inhibit Human Carbonic Anhydrase IX and XII

by Kerem Buran, Silvia Bua, Giulio Poli, F. Esra Önen Bayram, Tiziano Tuccinardi and Claudiu T. Supuran

Int. J. Mol. Sci. 2019, 20(5), 1208; https://doi.org/10.3390/ijms20051208 - 10 Mar 2019

Cited by 27 | Viewed by 4272

Abstract

A novel series of 8-substituted coumarin-based compounds, characterized by the presence of alkylpiperazine and arylpiperazine chains, were synthesized and tested for their inhibitory activity against four human carbonic anhydrase (hCA) isoforms. All compounds displayed nanomolar potency against the cancer-related hCA IX and hCA XII; moreover, they were shown to be devoid of any inhibitory activity toward the cytosolic hCA I and hCA II up to 10 µM concentration in the assay system. Therefore, the synthesized coumarin ligands demonstrated to be potent and selective hCA IX/XII inhibitors, and were shown to be as potent as the reference inhibitor acetazolamide against hCA XII, with single-digit nanomolar K_i values. Molecular modeling studies provided a rationale for explaining the selectivity profile of these non-classic hCA inhibitors and their interactions with the enzymes, according to their specific mechanism of action, thus paving the way for future structure-based lead optimization studies. Full article

(This article belongs to the Special Issue Protease and Carbonic Anhydrase Inhibitors, II)

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