Synthesis, Antitumor Activity, and <i>In Silico</i> Drug Design of New Thieno[2,3-<i>d</i>]Pyrimidine-4-One Derivatives as Nonclassical Lipophilic Dihydrofolate Reductase Inhibitors

Abdelaziz, Ola A.; Husseiny, Walaa M. El; Selim, Khalid B.; Eisa, Hassan M.

doi:10.1021/acsomega.2c06078

Cited by 5 publications

(4 citation statements)

References 29 publications

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“…In 2022 [66], a team of researchers successfully prepare N′-(4-fluorobenzylidene)-2-[(4-oxo-3-phenyl-6,7,8,9tetrahydro-3H-cyclohepta- [4,5]thieno [2,3-d] Several thiazolopyrimidine derivatives were developed and tested for their ability to destroy cancer cells in the same year [69]. These were tested against three distinct human cancer cell types: MCF-7, A-549, and A-498, which represent non-small cell lung cancer, renal carcinoma, and breast cancer, with IC50 values of 2 µM for MCF-7 and A-549, and 1 µM for A-498, Compound 74 stood out among these as a very potent anticancer drug.…”

Section: Introductionmentioning

confidence: 99%

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Review: Pyrimidine Derivatives as Anticancer Agents

Helwa,

Ryad,

Youssef

et al. 2024

Journal of Pharmaceutical Sciences and Drug Manufacturing

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Cancer is a disease that can be fatal everywhere. It can start in almost any organ or tissue of the body when abnormal cells grow uncontrollably; they go further than their usual boundaries to attack contiguous parts of the body and/or slap-up meal to other organs. The primary problem facing current treatment techniques, such as chemotherapy and radiation, is multidrug resistance (MDR). Finding a unique and varied structural framework could open the door to the creation of fresh, potent anticancer medications. Also, the knowledge in genomics and molecular sciences has helped in creating drug targets. Pyrimidines, a class of nitrogen-containing heterocyclic compounds, play a significant role in crafting cancer treatment drugs. These synthetic compounds have proven effective against various cancers, including myeloid leukemia, breast cancer, liver cancer, pancreatic cancer, and idiopathic pulmonary fibrosis. This review presents the findings of several investigations conducted between 2006 and 2023 on pyrimidine derivatives and their corresponding anticancer characteristics.

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Section: Introductionmentioning

confidence: 99%

“…Journal of Pharmaceutical Sciences and Drug Manufacturing 1 (2024)[54][55][56][57][58][59][60][61][62][63][64][65][66][67][68] …”

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confidence: 99%

Review: Pyrimidine Derivatives as Anticancer Agents

Helwa,

Ryad,

Youssef

et al. 2024

Journal of Pharmaceutical Sciences and Drug Manufacturing

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“…The thienopyrimidinone framework is widely documented in many biologically active compounds such as anti-tumor [ 33 ], anti-malarial [ 34 , 35 ], anti-microbial and anti-fungal [ 36 ], anti-inflammatory [ 37 ] and anti-tubercular [ 38 ] agents.…”

Section: Introductionmentioning

confidence: 99%

Dihydroxyphenyl- and Heteroaromatic-Based Thienopyrimidinones to Tackle HIV-1 LEDGF/p75-Dependent IN Activity

Tocco,

Canton,

Laus

et al. 2023

Molecules

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The spread of Human Immunodeficiency Virus (HIV) still represents a global public health issue of major concern, and would benefit from unveiling unique viral features as targets for drug design. In this respect, HIV-1 integrase (IN), due to the absence of homologs in human cells, is a popular target for the synthesis of novel selective compounds. Moreover, as drug-resistant viral strains are rapidly evolving, the development of novel allosteric inhibitors is acutely required. Recently, we have observed that Kuwanon-L, quinazolinones and thienopyrimidinones containing at least one polyphenol unit, effectively inhibited HIV-1 IN activity. Thus, in the present research, novel dihydroxyphenyl-based thienopyrimidinone derivatives were investigated for their LEDGF/p75-dependent IN inhibitory activity. Our findings indicated a close correlation between the position of the OH group on the phenyl moiety and IN inhibitory activity of these compounds. As catechol may be involved in cytotoxicity, its replacement by other aromatic scaffolds was also exploited. As a result, compounds 21–23, 25 and 26 with enhanced IN inhibitory activity provided good lead candidates, with 25 being the most selective for IN. Lastly, UV spectrometric experiments suggested a plausible allosteric mode of action, as none of the thienopirimidinones showed Mg2+ chelation properties otherwise typical of IN strand transfer inhibitors (INSTIs).

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“…Therefore, development of novel antifolates remains relevant and has interest for various research groups [2,5,[6][7][8][9][10][11]. Thieno [2,3-d]pyrimidine heterocycle also attracts attention in that respect [12][13][14][15]. Thieno [2,3-d]pyrimidine scaffold with a linker attached to the position 6 of heterocycle provides a geometry similar but slightly different to that of folic acid as a sulfur atom is isosteric to two methine groups.…”

Section: Introductionmentioning

confidence: 99%

Synthesis and dihydrofolate reductase inhibitory activity of 2-amino-6-(arylaminomethyl) thieno[2,3-d]pyrimidin-4(3H)-ones

Dailidė,

Tumkevičius

2023

chemija

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The present work deals with synthesis and biological evaluation of novel compounds as potential inhibitors of dihydrofolate reductase (DHFR) from opportunistic microorganisms – Pneumocystis carinii (pc), Toxoplasma gondii (tg) and Mycobacterium avium (ma). A set of 6 lipophilic and 1 classical antifolates of thieno[2,3-d]pyrimidine series were designed and synthesised with key pharmacophoric features of DHFR inhibitors and aminomethylene bridge joining the aromatic part and 2-amino-4-oxothieno[2,3-d]pyrimidine nucleus. Investigation of the DHFR inhibitory activity of the synthesised compounds revealed that 2-amino-6-[(4-methoxyphenylamino)-, 6--[(4-chlorophenylamino)- and 6-[(2,5 ichlorophenylamino)methyl]thieno[2,3-d]pyrimidin-4(3H)- ones had a moderate activity (IC50 56.5, 49.9 and 23 μM, respectively) against pcDHFR. Activity of those compounds against tgDHFR (IC50 6.0, 2.8 and 2.3 μM, respectively) was comparable to that of trimethoprim (IC50 2.7 μM). No synthesised lipophilic antifolates showed activity towards maDHFR. The classical antifolate 2-{4-[(2-amino-4-oxo-3,4- dihydrothieno[2,3-d]pyrimidin-6-yl)methylamino]benzamido}-L-glutamic acid inhibited DHFRs from all microorganisms (IC50 6.6 μM for pcDHFR, 1.06 μM for tgDHFR and 16.9 μM for maDHFR).

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Synthesis, Antitumor Activity, and In Silico Drug Design of New Thieno[2,3-d]Pyrimidine-4-One Derivatives as Nonclassical Lipophilic Dihydrofolate Reductase Inhibitors

Cited by 5 publications

References 29 publications

Review: Pyrimidine Derivatives as Anticancer Agents

Review: Pyrimidine Derivatives as Anticancer Agents

Dihydroxyphenyl- and Heteroaromatic-Based Thienopyrimidinones to Tackle HIV-1 LEDGF/p75-Dependent IN Activity

Synthesis and dihydrofolate reductase inhibitory activity of 2-amino-6-(arylaminomethyl) thieno[2,3-d]pyrimidin-4(3H)-ones

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