Quest for a potent antimalarial drug lead: Synthesis and evaluation of 6,7-dimethoxyquinazoline-2,4-diamines

Mizukawa, Yuki; Ikegami-Kawai, Mayumi; Horiuchi, Masako; Kaiser, Marcel; Kojima, M.; Sakanoue, Seiki; Miyagi, Seiya; Chick, Christian Nanga; Togashi, Hiroyuki; Tsubuki, Masayoshi; Ihara, Masataka; Usuki, Toyonobu; Itoh, Isamu

doi:10.1016/j.bmc.2021.116018

Cited by 13 publications

(10 citation statements)

References 12 publications

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“…The scaffold was found to have antimalarial activity in a large screen by GSK and subsequently included in the Tres Cantos Antimalarial Set (TCAMS) 9 . Since then, the scaffold has been extensively optimized and found to have multistage activity 206–209 . Despite this, the precise targets of the scaffold remain unclear.…”

Section: Chemical Probesmentioning

confidence: 99%

Chemo‐proteomics in antimalarial target identification and engagement

Bailey

Nguyen

Cowman

et al. 2023

Medicinal Research Reviews

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Humans have lived in tenuous battle with malaria over millennia. Today, while much of the world is free of the disease, areas of South America, Asia, and Africa still wage this war with substantial impacts on their social and economic development. The threat of widespread resistance to all currently available antimalarial therapies continues to raise concern. Therefore, it is imperative that novel antimalarial chemotypes be developed to populate the pipeline going forward. Phenotypic screening has been responsible for the majority of the new chemotypes emerging in the past few decades. However, this can result in limited information on the molecular target of these compounds which may serve as an unknown variable complicating their progression into clinical development. Target identification and validation is a process that incorporates techniques from a range of different disciplines. Chemical biology and more specifically chemo‐proteomics have been heavily utilized for this purpose. This review provides an in‐depth summary of the application of chemo‐proteomics in antimalarial development. Here we focus particularly on the methodology, practicalities, merits, and limitations of designing these experiments. Together this provides learnings on the future use of chemo‐proteomics in antimalarial development.

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Section: Chemical Probesmentioning

confidence: 99%

Chemo‐proteomics in antimalarial target identification and engagement

Bailey

Nguyen

Cowman

et al. 2023

Medicinal Research Reviews

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“…2‐Aminopyrimidines constitute an important derivative class of pyrimidine, and have been interested in design and synthesis with applications in biology and medicinal chemistry. Numerous pyrimidine‐based derivatives express remarkable biological activity, such as antimicrobial (Almeida et al., 2021), anticancer (Filho et al., 2021), antimalarial (Mizukawa et al., 2021), neuro‐degeneration diseases (Liu et al., 2020), enzyme inhibitors against phosphodiesterase (Nadur et al., 2021), HIV‐1 reverse transcriptase (Gu et al., 2020), and carbonic anhydrase (Abdel‐Mohsen et al., 2022) activities. Several sulfonamides bearing pyrimidine moiety exhibit carbonic anhydrase inhibitory action (Manzoor et al., 2021).…”

Section: Introductionmentioning

confidence: 99%

Sulfonyl thiourea derivatives from 2‐aminodiarylpyrimidines: In vitro and in silico evaluation as potential carbonic anhydrase I, II, IX, and XII inhibitors

Thanh,

Giang,

Hai

et al. 2024

Chem Biol Drug Des

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A series of synthesized sulfonyl thiourea derivatives (7a–o) of substituted 2‐amino‐4,6‐diarylpyrimidines (4a–o) exhibited the remarkable inhibitory activity against some the human carbonic anhydrases (hCAs), including hCA I, II, IX, and XII isoforms. The inhibitory efficacy of synthesized sulfonyl thiourea derivatives were experimentally validated by in vitro enzymatic assays. 7a (KI = 46.14 nM), 7j (KI = 48.92 nM), and 7m (KI = 62.59 nM) (for isoform hCA I); 7f (KI = 42.72 nM), 7i (KI = 40.98 nM), and 7j (KI = 33.40 nM) (for isoform hCA II); 7j (KI = 228.5 nM), 7m (KI = 195.4 nM), and 7n (KI = 210.1 nM) (for isoform hCA IX); 7l (KI = 116.9 nM), 7m (KI = 118.8 nM), and 7n (KI = 147.2 nM) (for isoform hCA XII) in comparison with KI values of 452.1, 327.3, 437.2, and 338.9 nM, respectively, of the standard drug AAZ. These compounds also had significantly more potent inhibitory action against cytosolic isoform hCA I and tumor‐associated isoforms hCA IX and hCA XII. Furthermore, the potential inhibitory compounds were subjected to in silico screening for molecular docking and molecular dynamics simulations. The results of in vitro and in silico studies revealed that compounds 7a, 7j, and 7m were the most promising derivatives in this series due to their significant effects on studied hCA I, II, IX, and XII isoforms, respectively. The results showed that the sulfonyl thiourea moiety was accommodated deeply in the active site and interacted with the zinc ion in the receptors.

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“…Approximately 150 different 6,7-dimethoxyquinazoline-2,4-diamines were synthesized, and via structure-activity relationship studies. Among them 6,7-dimethoxy-N4-(1-phenylethyl)-2-(pyrrolidin-1-yl)quinazo-lin-4-amine exhibits high antimalarial activity as a promising antimalarial drug lead [24]. Two new series of synthesized quinazolinone derivatives were investigated as potential future antileishmanial agents, by assessing their activities against the Leishmania (L.) donovani and L. major species.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and evaluation of cerebroprotective activity of novel 6,7-dimethoxyquinazolin-4(3H)-one derivatives containing residues of amino acids and dipeptides

2022

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Neurodegenerative processes of the central nervous system are an important socially significant problem of modern society. They cause many diseases, such as Alzheimer's disease and cerebral ischemia, which significantly reduce the quality of human life and can lead to disability or death. The aim of this study was to synthesize novel 6,7-dimethoxyquinazolin-4(3H)-one derivatives with the remains of neuroactive amino acids and dipeptides in order to investigate their cerebroprotective properties. As a result of the study, 13 novel 6,7-dimetho-xyquinazolin-4(3H)-one derivatives were synthesized. Cerebral ischemia in rats was reproduced by irreversible right-sided occlusion of the middle cerebral artery using the Tamura method, and the area of brain necrosis was evaluated. Cognitive functions were evaluated in the Y-maze test. Among the studied quinazolinone derivatives, compounds 3i, 3j and 3k have the most pronounced cerebrotropic activity, which is not inferior to ethylmethylhydroxypyridine succinate in terms of pharmacological activity, making them promising objects for further research.

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Quest for a potent antimalarial drug lead: Synthesis and evaluation of 6,7-dimethoxyquinazoline-2,4-diamines

Cited by 13 publications

References 12 publications

Chemo‐proteomics in antimalarial target identification and engagement

Chemo‐proteomics in antimalarial target identification and engagement

Sulfonyl thiourea derivatives from 2‐aminodiarylpyrimidines: In vitro and in silico evaluation as potential carbonic anhydrase I, II, IX, and XII inhibitors

Synthesis and evaluation of cerebroprotective activity of novel 6,7-dimethoxyquinazolin-4(3H)-one derivatives containing residues of amino acids and dipeptides

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