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Chemistry & Biodiversity Sep 2022[1,2,4]Triazolo[1,5-a]pyrimidine is an important heterocyclic scaffold known to have a wide range of pharmacological activities such as anticancer, antimicrobial,... (Review)
Review
[1,2,4]Triazolo[1,5-a]pyrimidine is an important heterocyclic scaffold known to have a wide range of pharmacological activities such as anticancer, antimicrobial, anti-tubercular, CB cannabinoid agonists, feticide, and adenosine antagonists. Several clinical trials and marketed drugs such as Trapidil, Essramycin, Pyroxsulam, DSM-265, Flumetsulam, GNF-6702, and Cevipabulin indicate the potential of [1,2,4]triazolo[1,5-a]pyrimidine moiety with various functional groups in medicinal chemistry. Herein, we represent a concise report focusing on the synthetic strategies used for diversely substituted [1,2,4]triazolo[1,5-a]pyrimidine analogs and their pharmacological applications. To the best of our knowledge, since 1980, we are the first to write a review on this emerging scaffold, which reveals the synthetic strategies, and pharmacological activities of differently substituted [1,2,4]triazolo[1,5-a]pyrimidine with special emphasis on structure-activity relationship studies.
Topics: Adenosine; Anti-Infective Agents; Cannabinoid Receptor Agonists; Pyrimidines; Structure-Activity Relationship; Trapidil
PubMed: 35946991
DOI: 10.1002/cbdv.202200291 -
ChemMedChem Jan 2022Five focused libraries of pyrimidine-based dynamin GTPase inhibitors, in total 69 compounds were synthesised, and their dynamin inhibition and broad-spectrum...
Five focused libraries of pyrimidine-based dynamin GTPase inhibitors, in total 69 compounds were synthesised, and their dynamin inhibition and broad-spectrum cytotoxicity examined. Dynamin plays a crucial role in mitosis, and as such inhibition of dynamin was expected to broadly correlate with the observed cytotoxicity. The pyrimidines synthesised ranged from mono-substituted to trisubstituted. The highest levels of dynamin inhibition were noted with di- and tri- substituted pyrimidines, especially those with pendent amino alkyl chains. Short chains and simple heterocyclic rings reduced dynamin activity. There were three levels of dynamin activity noted: 1-10, 10-25 and 25-60 μM. Screening of these compounds in a panel of cancer cell lines: SW480 (colon), HT29 (colon), SMA (spontaneous murine astrocytoma), MCF-7 (breast), BE2-C (glioblastoma), SJ-G2 (neuroblastoma), MIA (pancreas), A2780 (ovarian), A431 (skin), H460 (lung), U87 (glioblastoma) and DU145 (prostate) cell lines reveal a good correlation between the observed dynamin inhibition and the observed cytotoxicity. The most active analogues (31 a,b) developed returned average GI values of 1.0 and 0.78 μM across the twelve cell lines examined. These active analogues were: N -(3-dimethylaminopropyl)-N -dodecyl-6-methylpyrimidine-2,4-diamine (31 a) and N -(3-dimethylaminopropyl)-N -dodecyl-6-methylpyrimidine-2,4-diamine (31 b).
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cytotoxins; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Dynamins; Enzyme Inhibitors; Humans; Molecular Structure; Pyrimidines; Structure-Activity Relationship
PubMed: 34590434
DOI: 10.1002/cmdc.202100560 -
Mycoses Oct 2020Invasive fungal infections (IFIs) in the central nervous system (CNS) are particularly hard to treat and are associated with high morbidity and mortality rates. Four... (Review)
Review
Invasive fungal infections (IFIs) in the central nervous system (CNS) are particularly hard to treat and are associated with high morbidity and mortality rates. Four chemical classes of systemic antifungal agents are used for the treatment of IFIs (eg meningitis), including polyenes, triazoles, pyrimidine analogues and echinocandins. This review will address all of these classes and discuss their penetration and accumulation in the CNS. Treatment of fungal meningitis is based on the antifungal that shows good penetration and accumulation in the CNS. Pharmacokinetic data concerning the entry of antifungal agents into the intracranial compartments are faulty. This review will provide an overview of the ability of systemic antifungals to penetrate the CNS, based on previously published drug physicochemical properties and pharmacokinetic data, for evaluation of the most promising antifungal drugs for the treatment of fungal CNS infections. The studies selected and discussed in this review are from 1990 to 2019.
Topics: Antifungal Agents; Central Nervous System Fungal Infections; Echinocandins; Humans; Invasive Fungal Infections; Meningitis, Fungal; Polyenes; Pyrimidines; Triazoles
PubMed: 32772402
DOI: 10.1111/myc.13157 -
Advances in Experimental Medicine and... 2016The carbon 5 of pyrimidine nucleobases is a privileged position in terms of nucleoside modification in both DNA and RNA. The simplest modification of uridine at this... (Review)
Review
The carbon 5 of pyrimidine nucleobases is a privileged position in terms of nucleoside modification in both DNA and RNA. The simplest modification of uridine at this position is methylation leading to thymine. Thymine is an integral part of the standard nucleobase repertoire of DNA that is synthesized at the nucleotide level. However, it also occurs in RNA, where it is synthesized posttranscriptionally at the polynucleotide level. The cytidine analogue 5-methylcytidine also occurs in both DNA and RNA, but is introduced at the polynucleotide level in both cases. The same applies to a plethora of additional derivatives found in nature, resulting either from a direct modification of the 5-position by electrophiles or by further derivatization of the 5-methylpyrimidines. Here, we review the structural diversity of these modified bases, the variety of cofactors that serve as carbon donors, and the common principles shared by enzymatic mechanisms generating them.
Topics: Alkylation; Carbon; Cytidine; DNA; DNA Methylation; Molecular Structure; Pyrimidine Nucleosides; RNA; Thymidylate Synthase; Uridine
PubMed: 27826833
DOI: 10.1007/978-3-319-43624-1_2 -
Clinical Pharmacokinetics Dec 2020Pyrimidine analogues can be considered as prodrugs, like their natural counterparts, they have to be activated within the cell. The intracellular activation involves... (Review)
Review
Pyrimidine analogues can be considered as prodrugs, like their natural counterparts, they have to be activated within the cell. The intracellular activation involves several metabolic steps including sequential phosphorylation to its monophosphate, diphosphate and triphosphate. The intracellularly formed nucleotides are responsible for the pharmacological effects. This review provides a comprehensive overview of the clinical studies that measured the intracellular nucleotide concentrations of pyrimidine analogues in patients with cancer. The objective was to gain more insight into the parallels between the different pyrimidine analogues considering their intracellular pharmacokinetics. For cytarabine and gemcitabine, the intracellular pharmacokinetics have been extensively studied over the years. However, for 5-fluorouracil, capecitabine, azacitidine and decitabine, the intracellular pharmacokinetics was only very minimally investigated. This is probably owing to the fact that there were no suitable bioanalytical assays for a long time. Since the advent of suitable assays, the first exploratory studies indicate that the intracellular 5-fluorouracil, azacitidine and decitabine nucleotide concentrations are very low compared with the intracellular nucleotide concentrations obtained during treatment with cytarabine or gemcitabine. Based on their pharmacology, the intracellular accumulation of nucleotides appears critical to the cytotoxicity of pyrimidine analogues. However, not many clinical studies have actually investigated the relationship between the intracellular nucleotide concentrations in patients with cancer and the anti-tumour effect. Only for cytarabine, a relationship was demonstrated between the intracellular triphosphate concentrations in leukaemic cells and the response rate in patients with AML. Future clinical studies should show, for the other pyrimidine analogues, whether there is a relationship between the intracellular nucleotide concentrations and the clinical outcome of patients. Research that examined the intracellular pharmacokinetics of cytarabine and gemcitabine focused primarily on the saturation aspect of the intracellular triphosphate formation. Attempts to improve the dosing regimen of gemcitabine were aimed at maximising the intracellular gemcitabine triphosphate concentrations. However, this strategy does not make sense, as efficient administration also means that less gemcitabine can be administered before dose-limiting toxicities are achieved. For all pyrimidine analogues, a linear relationship was found between the dose and the plasma concentration. However, no correlation was found between the plasma concentration and the intracellular nucleotide concentration. The concentration-time curves for the intracellular nucleotides showed considerable inter-individual variation. Therefore, the question arises whether pyrimidine analogue therapy should be more individualised. Future research should show which intracellular nucleotide concentrations are worth pursuing and whether dose individualisation is useful to achieve these concentrations.
Topics: Cytarabine; Deoxycytidine; Fluorouracil; Humans; Neoplasms; Phosphorylation; Prodrugs; Pyrimidines; Gemcitabine
PubMed: 33064276
DOI: 10.1007/s40262-020-00934-7 -
Mini Reviews in Medicinal Chemistry 2020Cancer is the world's second-largest cause of mortality and one of the biggest global health concerns. The prevalence and mortality rates of cancer remain high despite... (Review)
Review
Cancer is the world's second-largest cause of mortality and one of the biggest global health concerns. The prevalence and mortality rates of cancer remain high despite significant progress in cancer therapy. The search for more effective, as well as less toxic treatment methods for cancer, is at the focus of current studies. Thiophene and its derivatives have surged as an influential scaffold, which, because of their appreciable diversity in biological activities, has drawn the concerned interest of the researchers in the field of medicinal chemistry. By the affluent introduction of its derivatives, which have antioxidant, anti-inflammatory, antimicrobial, and anticancer activities, the adaptability of the thiophene moiety has been displayed. The nature and positioning of the substitutions significantly impacted thiophene moiety activity. This decent array in the living response account about this moiety has picked plentiful researcher's consideration to inquire about it to its peculiar potential across certain activities. In the field of cancer therapy against different cancer cells, the structure-activity relationship for each of the derivatives showed an excellent understanding of thiophene moiety. Information from the various articles revealed the key role of thiophene moiety and its derivatives to develop the vital lead compound. The essential anticancer mechanisms identified include inhibition of the topoisomerase, inhibition of tyrosine kinase, tubulin interaction and apoptosis induction through the activation of reactive oxygen species. This review is an endeavor to promote the anticancer potential of the derivatives, whether having thiophene or condensed thiophene as a core moiety or as a substituent that can lead in the future to synthesize varieties of chemotherapeutic entities in the field of cancer treatment.
Topics: Antineoplastic Agents; Cell Proliferation; Drug Screening Assays, Antitumor; Humans; Neoplasms; Pyrimidines; Structure-Activity Relationship; Thiophenes
PubMed: 32669077
DOI: 10.2174/1389557520666200715104555 -
Anti-cancer Agents in Medicinal... Aug 2022Cancer has emerged as one of the leading causes of death globally, partly due to the steady rise in anticancer drug resistance. Pyrimidine and pyrimidine-fused... (Review)
Review
Cancer has emerged as one of the leading causes of death globally, partly due to the steady rise in anticancer drug resistance. Pyrimidine and pyrimidine-fused heterocycles are some of the privileged scaffolds in medicine, as they possess diverse biological properties. Pyrimidines containing azole nucleus possess inestimable anticancer potency and can potentially regulate cellular pathways for selective anticancer activity. The present review outlines the molecular structure of pyrimidine-fused azoles with significant anticancer activity. The structure activity relationship and molecular docking studies have also been discussed. The current review is the first complete compilation of significant literature on the proposed topic from 2016 to 2020. The information contained in this review offers a useful insight to chemists in the design of new and potent anticancer azole-pyrimidine analogues.
Topics: Antineoplastic Agents; Azoles; Humans; Molecular Docking Simulation; Molecular Structure; Pyrimidines; Structure-Activity Relationship
PubMed: 35306990
DOI: 10.2174/1871520622666220318090147 -
Journal of Medicinal Chemistry Dec 2023MA (-methyladenosine) plays a significant role in regulating RNA processing, splicing, nucleation, translation, and stability. AlkB homologue 5 (ALKBH5) is an...
MA (-methyladenosine) plays a significant role in regulating RNA processing, splicing, nucleation, translation, and stability. AlkB homologue 5 (ALKBH5) is an Fe(II)/2-oxoglutarate (2-OG)-dependent dioxygenase that demethylates mono- or dimethylated adenosines. ALKBH5 can be regarded as an oncogenic factor for various human cancers. However, the discovery of potent and selective ALKBH5 inhibitors remains a challenge. We identified as a novel and selective inhibitor of ALKBH5 by structure-based virtual screening and optimization. was not a 2-oxoglutarate analogue and could selectively inhibit the demethylase activity of ALKBH5 over FTO. increased the abundance of mA modifications in AML cells, reduced the mRNA stability of , and inhibited cell cycle progression. Furthermore, significantly suppressed tumor growth in the MV4-11 xenograft mouse model and showed a favorable safety profile. Collectively, our results highlight the development of a selective probe for ALKBH5 that will pave the way for the further study of ALKBH5 targeting therapies.
Topics: Humans; Mice; Animals; Ketoglutaric Acids; Dioxygenases; Pyrimidines; Leukemia, Myeloid, Acute; AlkB Homolog 5, RNA Demethylase; Microtubule-Associated Proteins; Alpha-Ketoglutarate-Dependent Dioxygenase FTO
PubMed: 37983486
DOI: 10.1021/acs.jmedchem.3c01374 -
ChemMedChem Mar 2021Neglected tropical diseases remain among the most critical public health concerns in Africa and South America. The drug treatments for these diseases are limited, which...
Neglected tropical diseases remain among the most critical public health concerns in Africa and South America. The drug treatments for these diseases are limited, which invariably leads to fatal cases. Hence, there is an urgent need for new antitrypanosomal drugs. To address this issue, a large number of diverse heterocyclic compounds were prepared. Straightforward synthetic approaches tolerated pre-functionalized structures, giving rise to a structurally diverse set of analogs. We report on a set of 57 heterocyclic compounds with selective activity potential against kinetoplastid parasites. In general, 29 and 19 compounds of the total set could be defined as active against Trypanosoma cruzi and T. brucei brucei, respectively (antitrypanosomal activities <10 μM). The present work discusses the structure-activity relationships of new fused-ring scaffolds based on imidazopyridine/pyrimidine and furopyridine cores. This library of compounds shows significant potential for anti-trypanosomiases drug discovery.
Topics: Dose-Response Relationship, Drug; Humans; Imidazoles; Molecular Structure; Parasitic Sensitivity Tests; Pyridines; Pyrimidines; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosoma cruzi; Trypanosomiasis
PubMed: 33078573
DOI: 10.1002/cmdc.202000616 -
Bioorganic Chemistry Sep 2021This study was focused on the synthesis of new pyrimidines 4a,b, 5a,b and pyrazoles 6a, b as ATP mimicking tyrosine kinase inhibitors of the epidermal growth factor...
This study was focused on the synthesis of new pyrimidines 4a,b, 5a,b and pyrazoles 6a, b as ATP mimicking tyrosine kinase inhibitors of the epidermal growth factor receptor (EGFR). The new compounds were assessed as cytotoxic candidates against human breast cancer cells (MCF-7) and hepatocellular carcinoma cells (HepG-2). All the new compounds appeared as more potent cytotoxic agents than erlotinib, while only compound 4a exhibited more potency than 5-flourouracil and 4b analogue was equipotent to it. Accordingly, the kinase suppression effect of 4a and 4b was further evaluated against EGFR, EGFR and EGFR. Both pyrimidine analogues 4a and 4b displayed outstanding inhibitory activity against EGFR and its two mutated isoforms EGFR and EGFR in comparing to erlotinib and osimertinib as reference drugs. Additionally, all the new analogues were subjected to antimicrobial assay. Interestingly, both 4a and 4b represented the most promising activity of wide spectrum antimicrobial effect against the examined microbes in comparison to gentamycin and ketoconazole as standard drugs. Moreover, docking results proved the good binding interactions of the compounds 4a and 4b with EGFR and EGFR which were in accordance with the results of the in vitro enzyme assay. Additional in silico ADMET studies were performed for the new derivatives which represented their good oral absorption, good drug-likeness properties and low toxicity risks in human.
Topics: Anti-Bacterial Agents; Antifungal Agents; Antineoplastic Agents; Aspergillus fumigatus; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; ErbB Receptors; Humans; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; Mucorales; Protein Kinase Inhibitors; Proteus vulgaris; Pyrazoles; Pyrimidines; Streptococcus; Structure-Activity Relationship
PubMed: 34161878
DOI: 10.1016/j.bioorg.2021.105078