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10 pages, 3901 KiB

Open AccessCommunication

An Alternative Method for Synthesizing N,2,3-Trimethyl-2H-indazol-6-amine as a Key Component in the Preparation of Pazopanib

by Thi Thanh Cham Bui, Hue Linh Luu, Thi Thanh Luong, Thi Ngoc Nguyen, Nguyet Suong Huyen Dao, Van Giang Nguyen, Dinh Luyen Nguyen, Nguyen Trieu Trinh and Van Hai Nguyen

Chemistry 2024, 6(5), 1089-1098; https://doi.org/10.3390/chemistry6050063 - 19 Sep 2024

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Abstract

Due to its application as an anti-cancer drug, pazopanib (1) has attracted the interest of many researchers, and several studies on pazopanib synthesis have been reported over the years. This paper provides a novel route for synthesizing N,2,3-trimethyl-2H-indazol-6-amine (5), which is a crucial building block in the synthesis of pazopanib from 3-methyl-6-nitro-1H-indazole (6). By alternating between the reduction and two methylation steps, compound 5 was obtained in a yield comparable (55%) to what has been reported (54%). It is noteworthy that the last step of N²-methylation also yielded N,N,2,3-tetramethyl-2H-indazol-6-amine (5′) as a novel compound. Furthermore, the data presented in this paper can serve as a valuable resource for future research aimed at further refining the process of synthesizing pazopanib and its derivatives. Full article

(This article belongs to the Section Medicinal Chemistry)

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11 pages, 4146 KiB

Open AccessCommunication

Synthesis and Characterization of Novel Indazole–Sulfonamide Compounds with Potential MAPK1 Inhibitory Activity for Cancer Treatment

by Nassima Saghdani, Abdelali Chihab, Nabil El Brahmi and Saïd El Kazzouli

Molbank 2024, 2024(3), M1858; https://doi.org/10.3390/M1858 - 26 Jul 2024

Cited by 2 | Viewed by 2473

Abstract

Indazoles are a very important group of nitrogen-containing heterocycles with a wide range of biological and medicinal applications. These properties make them highly attractive for drug development, particularly when combined with sulfonamides to enhance their medicinal potential. In this work, we synthesized an indazole-based sulfonamide, namely the 1-((2-chloro-5-methoxyphenyl)sulfonyl)-5-nitro-1H-indazole (3). The reduction of the nitro group of 5-nitroindazole (1) to its corresponding amine was also performed to yield compound (4). Both compounds’ structures were elucidated using various spectroscopic techniques such as ¹H NMR, ¹³C NMR, infrared (IR), and high-resolution mass spectrometry (HRMS). Our molecular docking studies suggest that compounds (3) and (4) have a strong affinity for MAPK1, indicating their potential as cancer treatments. Full article

(This article belongs to the Collection Heterocycle Reactions)

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10 pages, 2042 KiB

Open AccessArticle

Practical Synthesis of 7-Bromo-4-chloro-1H-indazol-3-amine: An Important Intermediate to Lenacapavir

by Naeem Asad, Michael Lyons, Shirley Muniz Machado Rodrigues, Justina M. Burns, Thomas D. Roper, G. Michael Laidlaw, Saeed Ahmad, B. Frank Gupton, Douglas Klumpp and Limei Jin

Molecules 2024, 29(12), 2705; https://doi.org/10.3390/molecules29122705 - 7 Jun 2024

Cited by 2 | Viewed by 3043

Abstract

7-Bromo-4-chloro-1H-indazol-3-amine is a heterocyclic fragment used in the synthesis of Lenacapavir, a potent capsid inhibitor for the treatment of HIV-1 infections. In this manuscript, we describe a new approach to synthesizing 7-bromo-4-chloro-1H-indazol-3-amine from inexpensive 2,6-dichlorobenzonitrile. This synthetic method utilizes a two-step sequence including regioselective bromination and heterocycle formation with hydrazine to give the desired product in an overall isolated yield of 38–45%. The new protocol has been successfully demonstrated on hundred-gram scales without the need for column chromatography purification. This new synthesis provides a potential economical route to the large-scale production of this heterocyclic fragment of Lenacapavir. Full article

(This article belongs to the Special Issue Synthesis of Heterocyclic Compounds via Cycloadditions: Applications in Medicinal Chemistry)

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12 pages, 6415 KiB

Open AccessArticle

Design, Synthesis and Antitumor Activity of 1H-indazole-3-amine Derivatives

by Congyu Wang, Mei Zhu, Xuesha Long, Qin Wang, Zhenchao Wang and Guiping Ouyang

Int. J. Mol. Sci. 2023, 24(10), 8686; https://doi.org/10.3390/ijms24108686 - 12 May 2023

Cited by 10 | Viewed by 3953

Abstract

A series of indazole derivatives were designed and synthesized by molecular hybridization strategy, and these compounds were evaluated the inhibitory activities against human cancer cell lines of lung (A549), chronic myeloid leukemia (K562), prostate (PC-3), and hepatoma (Hep-G2) by methyl thiazolyl tetrazolium (MTT) colorimetric assay. Among these, compound 6o exhibited a promising inhibitory effect against the K562 cell line with the IC₅₀ (50% inhibition concentration) value of 5.15 µM, and this compound showed great selectivity for normal cell (HEK-293, IC₅₀ = 33.2 µM). Moreover, compound 6o was confirmed to affect apoptosis and cell cycle possibly by inhibiting Bcl2 family members and the p53/MDM2 pathway in a concentration-dependent manner. Overall, this study indicates that compound 6o could be a promising scaffold to develop an effective and low-toxic anticancer agent. Full article

(This article belongs to the Special Issue New Advances on Photosensitiser or Inhibitors Molecules for Cancer Treatment)

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12 pages, 6564 KiB

Open AccessArticle

Optimization of 4-Anilinoquinolines as Dengue Virus Inhibitors

by Pei-Tzu Huang, Sirle Saul, Shirit Einav and Christopher R. M. Asquith

Molecules 2021, 26(23), 7338; https://doi.org/10.3390/molecules26237338 - 3 Dec 2021

Cited by 4 | Viewed by 3154

Abstract

Emerging viral infections, including those caused by dengue virus (DENV) and Venezuelan Equine Encephalitis virus (VEEV), pose a significant global health challenge. Here, we report the preparation and screening of a series of 4-anilinoquinoline libraries targeting DENV and VEEV. This effort generated a series of lead compounds, each occupying a distinct chemical space, including 3-((6-bromoquinolin-4-yl)amino)phenol (12), 6-bromo-N-(5-fluoro-1H-indazol-6-yl)quinolin-4-amine (50) and 6-((6-bromoquinolin-4-yl)amino)isoindolin-1-one (52), with EC₅₀ values of 0.63–0.69 µM for DENV infection. These compound libraries demonstrated very limited toxicity with CC₅₀ values greater than 10 µM in almost all cases. Additionally, the lead compounds were screened for activity against VEEV and demonstrated activity in the low single-digit micromolar range, with 50 and 52 demonstrating EC₅₀s of 2.3 µM and 3.6 µM, respectively. The promising results presented here highlight the potential to further refine this series in order to develop a clinical compound against DENV, VEEV, and potentially other emerging viral threats. Full article

(This article belongs to the Special Issue Antiviral Agents for RNA-Virus Infection)

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22 pages, 10011 KiB

Open AccessFeature PaperArticle

Towards the Development of an In vivo Chemical Probe for Cyclin G Associated Kinase (GAK)

by Christopher R. M. Asquith, James M. Bennett, Lianyong Su, Tuomo Laitinen, Jonathan M. Elkins, Julie E. Pickett, Carrow I. Wells, Zengbiao Li, Timothy M. Willson and William J. Zuercher

Molecules 2019, 24(22), 4016; https://doi.org/10.3390/molecules24224016 - 6 Nov 2019

Cited by 13 | Viewed by 4475

Abstract

SGC-GAK-1 (1) is a potent, selective, cell-active chemical probe for cyclin G-associated kinase (GAK). However, 1 was rapidly metabolized in mouse liver microsomes by cytochrome P450-mediated oxidation, displaying rapid clearance in liver microsomes and in mice, which limited its utility in in vivo studies. Chemical modifications of 1 that improved metabolic stability, generally resulted in decreased GAK potency. The best analog in terms of GAK activity in cells was 6-bromo-N-(1H-indazol-6-yl)quinolin-4-amine (35) (IC₅₀ = 1.4 μM), showing improved stability in liver microsomes while still maintaining a narrow spectrum activity across the kinome. As an alternative to scaffold modifications we also explored the use of the broad-spectrum cytochrome P450 inhibitor 1-aminobenzotriazole (ABT) to decrease intrinsic clearance of aminoquinoline GAK inhibitors. Taken together, these approaches point towards the development of an in vivo chemical probe for the dark kinase GAK. Full article

(This article belongs to the Special Issue Facing Novel Challenges in Drug Discovery)

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4 pages, 56 KiB

Open AccessShort Note

N¹-((1H-Indazol-5-yl)methylene)-N²-(2-((2-((2-(((1H-indazol-6-yl)methylene)amino)ethyl)amino)ethyl)amino)ethyl)ethane-1,2-diamine

by Cristina Núñez, Javier Fernández-Lodeiro, Adrián Fernández-Lodeiro, Emília Bértolo, José Luis Capelo and Carlos Lodeiro

Molbank 2012, 2012(3), M770; https://doi.org/10.3390/M770 - 9 Aug 2012

Viewed by 4552

Abstract

One novel molecular emissive probe L has been synthesized by classical Schiff-base reaction between 1H-indazole-6-carboxaldehyde and tetraethylenepentamine. The structure of compound L was confirmed by melting point, elemental analysis, ESI-MS spectrometry and by IR and ¹³C-NMR and ¹H-NMR spectroscopy. Full article

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