Therapeutic potential of heterocyclic pyrimidine scaffolds

Kumar, Sanjiv

doi:10.1186/s13065-018-0406-5

Cited by 149 publications

(88 citation statements)

References 62 publications

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“…The reactions took place both under conventional TH and MW irradiation, the use of MW having the advantages of obtaining slightly higher yields of the products and a substantial decrease of the reaction time from 8 h to 30 min. Using click chemistry (from the corresponding coumarin azide (48,50) and triple bond compounds), Kraljević et al [35] obtained 4-substituted 1,2,3-triazole coumarins 49a-p and 51a-f. The reaction took place under MW irradiation in good to very good yields (50 to 95%) and one hour reaction time.…”

Section: Five Membered Ring Azaheterocycles With More Than Two Heteromentioning

confidence: 99%

“…Using click chemistry (from the corresponding coumarin azide (48,50) and triple bond compounds), Kraljević et al [35] obtained 4-substituted 1,2,3-triazole coumarins 49a-p and 51a-f. The reaction took place under MW irradiation in good to very good yields (50 to 95%) and one hour reaction time.…”

Section: Five Membered Ring Azaheterocycles With More Than Two Heteromentioning

confidence: 99%

“…Compounds containing pyridine, pyridazine, pyrimidine, pyrazine, -and their fused derivatives-, are described to possess a wide range of biological activities, with these including antiviral, anti-HIV, antituberculosis, antimalarial, antileishmanial, antibacterial, antifungal, anti-inflammatory, anticancer, antihypertensive, diuretics, antiaggregative, antiplatelet, cardiotonics, antineurodegenerative, antidepressant, anxiolytics, anticonvulsivant, analgesic, sedatives, antiallergic, etc. [16,21,[40][41][42][43][44][45][46][47][48][49][50][51][52][53]. A large variety of syntheses are described for these compounds, with some of them using MW technology.…”

Section: Six Membered Ring Azaheterocyclesmentioning

confidence: 99%

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Microwave Assisted Reactions of Azaheterocycles Formedicinal Chemistry Applications

et al. 2020

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Microwave (MW) assisted reactions have became a powerful tool in azaheterocycles chemistry during the last decades. Five and six membered ring azaheterocycles are privileged scaffolds in modern medicinal chemistry possessing a large variety of biological activity. This review is focused on the recent relevant advances in the MW assisted reactions applied to azaheterocyclic derivatives and their medicinal chemistry applications from the last five years. The review is divided according to the main series of azaheterocycles, more precisely 5- and 6-membered ring azaheterocycles (with one, two, and more heteroatoms) and their fused analogues. In each case, the reaction pathways, the advantages of using MW, and considerations concerning biological activity of the obtained products were briefly presented.

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Section: Five Membered Ring Azaheterocycles With More Than Two Heteromentioning

confidence: 99%

Section: Five Membered Ring Azaheterocycles With More Than Two Heteromentioning

confidence: 99%

Section: Six Membered Ring Azaheterocyclesmentioning

confidence: 99%

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Microwave Assisted Reactions of Azaheterocycles Formedicinal Chemistry Applications

et al. 2020

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“…A small library of LSD1 inhibitors was acquired through commercial and collaborative sources or from information derived from a recent large-scale RNAi investigation of S. mansoni gene function [38] (Fig 1 and S1 Table). This collection included the only FDA-approved LSD1 inhibitor, trans-2-Phenylcyclopropylamine, (2-PCPA or better known as tranylcypromine (1) [35]), several small molecules undergoing clinical testing (including GSK-LSD1 (2) [39], ORY-1001 (3) [40] and GSK2879552 (8) [41]), pharmacologically active compounds synthesised around a substituted lysine scaffold (compounds 9 and 10 [42,43], the latter currently in clinical trial for the treatment of myelofibrosis [44]) and a selection of derivatised chemicals (compounds 11-38) [27,45]. This collection also included two dual LSD1/HDAC inhibitors (compounds 6 and 7) [26] designed as hybrid compounds resulting from the combination of a standard HDAC zinc binding group (benzamide group of Entinostat (MS-275) [46]) to either a phenelzine derivative (4, also known as Bizine [47]) or a cyclopropylamine analog of Bizine (5, [48]), respectively.…”

Section: Hslsd1 Inhibitors Differentially Affect Schistosomula Phenotmentioning

confidence: 99%

Schistosoma mansonilysine specific demethylase 1 (SmLSD1) is a druggable target involved in parasite survival, oviposition and stem cell proliferation

Padalino

Celatka²,

Rienhoff³

et al. 2020

Preprint

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Schistosomiasis is a chronically-debilitating neglected tropical disease (NTD) that predominantly affects people living in resource-poor communities of tropical and subtropical countries. Schistosoma mansoni, one of three species responsible for most human infections, undergoes strict developmental regulation of gene expression that is carefully controlled by both genetic- and epigenetic- processes. As inhibition of S. mansoni epigenetic machinery components has been shown to impair key transitions throughout the parasite’s digenetic lifecycle, this knowledge is currently fuelling the search for new epi-drug - based anthelmintics.In this study, the anti-schistosomal activity of 39 re-purposed Homo sapiens Lysine Specific Demethylase 1 (HsLSD1) inhibitors was investigated on key life cycle stages associated with both definitive (schistosomula, juvenile worms, sexually-mature adults) and intermediate host (miracidia) infection. The most active compound (compound 33; e.g. schistosomula phenotype EC50 = 4.370 µM; adult worm motility EC50 = 2.137 µM) was subsequently used to provide further insight into the critical role of S. mansoni lysine specific demethylase 1 (SmLSD1) in adult worm oviposition and stem cell proliferation. Here, compound 33 treatment of adult schistosomes led to significant defects in egg production, intra-egg vitellocyte/ovum packaging and gonadal/neoblast stem cell proliferation. A greater abundance of H3K4me2 marks accompanied these phenotypes and supported specific inhibition of SmLSD1 in adult schistosomes by compound 33. In silico screening indicated that compound 33 likely inhibits SmLSD1 activity by covalently reacting with the FAD cofactor.This work suggests that evaluation of HsLSD1 - targeting epi-drugs could have utility in the search for next-generation anti-schistosomals. The ability of compound 33 to inhibit parasite survival, oviposition, H3K4me2 demethylation and stem cell proliferation warrants further investigations of this compound and its epigenetic target. This data further highlights the importance of histone methylation in S. mansoni lifecycle transitions.Author summaryAffecting over 200 million people, schistosomiasis is a chronic disease caused by the parasitic worm Schistosoma mansoni. The frontline drug for schistosomiasis treatment is praziquantel. Owing to the concern surrounding praziquantel insensitivity or resistance developing, current research is directed towards the identification of novel drugs. We have focused our search for compounds that affect essential aspects of schistosome biology including parasite movement, fertility, cell proliferation and survival. Since all of these functions are potentially influenced by epigenetic regulation of gene expression, we investigated the activity of compounds that alter histone methylation status. In this report, we show that S. mansoni Lysine Specific Demethylase 1 (SmLSD1), a histone demethylase, is critical to miracidia-to-sporocyst transitioning, adult worm motility, egg production and parasite survival. Inhibition of SmLSD1 with compounds developed to inhibit the human paralog show promising potential as novel anti-schistosomal agents.

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“…Substituted pyrimidine derivatives (non-nucleosides) are found to be associated with various biological activities, including activity against different DNA and RNA viruses. 28 Previously, we showed that some pyrimidine derivatives have potent in vitro antiviral activity against polyovirus-3. 29 The present study focuses on the anti-BKV activity of pyrimidine derivatives which were synthesized at V.P.…”

Section: Introductionmentioning

confidence: 99%

In vitro anti-BK polyomavirus activity of imidazo[1,2-c]pyrimidine and pyrimido[1,6 a]pyrimidine derivatives

Solomyannyi¹,

Mitiukhin²,

Prichard³

et al. 2020

10.5267/j.ccl

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Five imidazo[1,2-c]pyrimidine and pyrimido[1,6-a]pyrimidine derivatives were designed, synthesized and evaluated for their antiproliferative activity and cytotoxicity. Primary bioassays in vitro showed that two of five synthesized compounds, 6-benzyl-8-(methylsulfonyl)-2,6-dihydroimidazo[1,2-c]pyrimidin-5(3H)-one, and 9-(methylsulfonyl)-7propyl-2,3,4,7-tetrahydro-6H-pyrimido[1,6-a]pyrimidin-6-one possessed potent antiviral activity against BKV (EC50: 0.66 μM and 0.96, respectively). The selectivity index of these compounds is similar to that of cidofovir. Although antiviral activity was evident in secondary assays, significant virus inhibition occurred at or near the cytotoxic concentration (SI90=1). Here we show that substituted pyrimidine derivatives are a promising structure class of chemical compounds for the development of antiviral drugs against BKV infections. Hence these compounds may be taken as lead compounds for further development of novel antimicrobial and anticancer agents.

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Therapeutic potential of heterocyclic pyrimidine scaffolds

Cited by 149 publications

References 62 publications

Microwave Assisted Reactions of Azaheterocycles Formedicinal Chemistry Applications

Microwave Assisted Reactions of Azaheterocycles Formedicinal Chemistry Applications

Schistosoma mansonilysine specific demethylase 1 (SmLSD1) is a druggable target involved in parasite survival, oviposition and stem cell proliferation

In vitro anti-BK polyomavirus activity of imidazo[1,2-c]pyrimidine and pyrimido[1,6 a]pyrimidine derivatives

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