A promising chromone-based compounds in drug discovery for new anti-inflammatory and anti-cancer drugs

Chromone, a group of heterocyclic compounds, has been recognised as a privileged structure for new drug discovery and development. These scaffolds have exhibited extensive acceptability due to their drug-like properties and versatile binding properties. Among several approved anti-inflammatory and anti-cancer drugs, these scaffolds show high selectivity for certain specific targets. For this reason, a significantly increasing number of research groups are interested in developing new synthetic methods and evaluating biological properties. In this view, we will discuss some of the important discoveries of chromone-based compounds as anti-inflammatory and anti-cancer agents, such as 2-(3,4-dimethoxyphenyl)-3-(4- fluorophenyl)-6-methoxy-4H-chromen-4-one (KR-1401-KW) which was found to be significantly active in suppressing PGE2-associated inflammatory responses and 3-(4-(chloromethyl)phenyl)-2-(3,4- dimethoxyphenyl)-7-methoxy-4H-chromen-4-one which was displayed potential inhibitor of UNC-51-like kinase 1 (ULK1) (KR-2201-NF) modulates autophagy and induces apoptosis in colon cancer. Moreover, computational evidence, including docking and molecular dynamics (MD) simulations, makes the compounds promising candidates for new anti-inflammatory and anti-cancer drugs

Synthesis of dihydropyrimidinone (DHPM) derivatives through a multicomponent reaction (MCR) and their biological activity

The spread of incurable diseases, especially infectious diseases caused by antibiotic-resistant bacteria and certain cancers, has become a serious public health concern. Consequently, the search for potent drug scaffolds has played an essential role in drug lead discovery. The multicomponent reaction (MCR) offers a novel method for efficient synthesis. It is rapidly evolving and is important for the discovery of novel molecules. We synthesized four dihydropyrimidinone (DHPM) derivatives with the one-pot MCR method, obtaining compounds 1-4. According to the NMR spectra analyses, compound 3 is a new derivative. In this experiment, we optimized the pH of the process. Based on the results, 1-4 had yields of 66.6, 72.9, 35.9, and 69.0%, respectively, at a pH of 4. In contrast, all yields significantly rose by 79.4, 91.9, 81.7, and 84.0% at pH 5. A pH of 5 was therefore advantageous for getting a high yield from these reactions. Compound 1 showed a significant inhibition against E. coli with an MIC value of 12.5 µg/mL with moderate activity against the breast cancer cell lines T47D and 4T1. Compound 3 was the most potent against S. aureus, with an MIC value of 25 µg/mL

BIOAKTIVITAS EKSTRAK KULIT BATANG TUMBUHAN LANGKA MERANTI LILIN

Tumbuhan Shorea teysmaniana Dier adalah tumbuhan khas Provinsi Riau yang sudah langka dan dikenal dengan nama Meranti Lilin. Kulit batang tumbuhan ini diekstrak dengan metoda maserasi, sehingga didapatka ekstrak heksan 40,69 g, ekstrak etilasetat 133,22 g, dan ekstrak methanol 386,29 g. Masing-masing ekstrak dilakukan uji antibakteri dengan metoda difusi dan uji anti oksidan dengan metoda DPPH. Uji antibakteri dilakukan terhadap bakteri Escherichia coli, Staphylococcus aureus, Sallmonella typhii, Bacillus subtilis dengan konsentrasi 1%. Ekstrak heksana tidak menunjukkan aktivitas, ekstrak etilasetat memberikan zona bening berturut-turut (mm) 13,2; 12,3; 9,6; 9;9. Ekstrak metanol menunjukkan aktifitas dg membentuk zona bening berturut-turut (mm) 10,6; 10,3; 8,1; 11,0. Berdasarkan aktivitas inilah proses isolasi dilanjutkan dengan menggunakan kromatografi vacum cair sehingga dihasilkan 12 fraksi untuk setiap ekstraknya. Ekstrak aktif dilanjutkan untuk diisolasi sampai senyawa murni, untuk ekstrak etil asetat menghasilkan 2 senyawa murni dengan kode HT1 dan HT2

Sintesis, penilaian biologi dan kajian dok sebatian auron ke atas enzim xantin oksidase

Perencatan aktiviti xantin oksidase (XO) merupakan satu pendekatan terapeutik yang berkesan dalam rawatan penyakit seperti gout dan hiperurikemia. Selain itu, penggunaan perencat XO juga dapat diluaskan kepada rawatan kecederaan contohnya reperfusi iskemia di pelbagai organ seperti jantung, hati dan buah pinggang. Dalam kajian ini, sebanyak 7 sebatian auron telah disintesis dan diuji ke atas XO dan dibandingkan dengan kawalan positif allopurinol. Sebatian 5e dikenalpasti sebagai sebatian yang paling berpotensi dan mampu merencatkan separuh daripada aktiviti XO pada 33.23 μM diikuti oleh sebatian 5f pada 210.22 μM dan sebatian 5d pada 302.0 μM. Kajian dok molekul telah dijalankan untuk memahami interaksi penting antara auron yang terpilih dengan tapak aktif XO

Palladium‐catalysed cross‐coupling reactions for the synthesis of chalcones

In this Minireview, we discuss some of the important palladium‐catalysed cross‐coupling reactions utilised in the synthesis of the enone system of chalcones. Examples given here not only exemplify the efficiency and practicality of new C−C bond formation of the enone system via palladium‐catalysed reactions but also reflect some of the revolutionary methods used for the preparation of a more complex and valuable chalcone scaffold which is known to be a privileged structure in the field of medicinal chemistry

Oestrogenic activity of mimosine on MCF-7 breast cancer cell line through the ERα-mediated pathway

Hormone replacement therapy has been a conventional treatment for postmenopausal symptoms in women. However, it has potential risks of breast and endometrial cancers. The aim of this study was to evaluate the oestrogenicity of a plant-based compound, mimosine, in MCF-7 cells by in silico model. Cell viability and proliferation, ERα-SRC1 coactivator activity and expression of specific ERα-dependent marker TFF1 and PGR genes were evaluated. Binding modes of 17β-oestradiol and mimosine at the ERα ligand binding domain were compared using docking and molecular dynamics simulation experiments followed by binding interaction free energy calculation with molecular mechanics/Poisson-Boltzmann surface area. Mimosine showed increased cellular viability (64,450 cells/ml) at 0.1 μM with significant cell proliferation (120.5%) compared to 17β-oestradiol (135.2%). ER antagonist tamoxifen significantly reduced proliferative activity mediated by mimosine (49.9%). Mimosine at 1 μM showed the highest ERα binding activity through increased SRC1 recruitment at 186.9%. It expressed TFF1 (11.1-fold at 0.1 μM) and PGR (13.9-fold at 0.01 μM) genes. ERα-mimosine binding energy was -49.9 kJ/mol, and it interacted with Thr347, Gly521 and His524 of ERα-LBD. The results suggested that mimosine has oestrogenic activity

Synthesis, In silico molecular docking modeling and pharmacophore mapping of (E)-3-(4-hydroxy-2,6-dimethoxyphenyl)-1-phenylprop-2-en-1- one as potential new inhibitor of microsomal prostaglandin E synthase-1

The discovery of potent anti-inflammatory agents through inhibition of prostaglandin E2 (PGE2) via microsomal prostaglandin E2 synthase-1 (mPGES-1) blocking has been proven to be an important game changer in pharmaceutical industry in recent years. In this study, new chalcone derivative has been successfully synthesized via Claisen-Schmidt condensation reaction. The compound was then docked into mPGES-1 active site to predict anti-inflammatory properties through ligand-enzyme interaction investigation. The data collected from in silico molecular docking simulation and pharmacophore modeling studies provide important insight on the molecular conformation and further shed light towards structural modification of the future novel mPGES-1 inhibitor

A mini-review on the insight into the effect of natural and Synthetic α,β-unsaturated carbonyl-containing compounds on PI3K/AKT/mTOR signaling pathways to treat breast cancer

Breast cancer, which has been one of the most frequently diagnosed cancers worldwide for decades, continues to defy treatment. While researching a remedy to this problem, it was discovered that mTOR has a strong association with breast cancer. Uncontrolled activation of mTOR is shown in a variety of different cancer, making it a critical target for cancer treatment. Inhibition of the mTOR protein kinase can cause autophagic cell death. It is known that covalent inhibitors have become a prominent issue in drug discovery, with covalent inhibitors focusing on �; �-unsaturated carbonyl molecules. Structural modifications to �; �-unsaturated carbonyl may be one of the finest avenues for developing the best breast cancer medication. This review article discusses recent research on natural and synthetic �; �-unsaturated carbonyls and their anti-cancer properties targeting on mTOR, with SAR to showcase the efficacy of synthetic natural products compared to parental compounds using both biological assays and in silico studies

A Mini-Review on the Insight into the Effect of Natural and Synthetic α,β-Unsaturated Carbonyl-Containing Compounds on PI3K/AKT/mTOR Signaling Pathways to Treat Breast Cancer

Breast cancer, which has been one of the most frequently diagnosed cancers worldwide for decades, continues to defy treatment. While researching a remedy to this problem, it was discovered that mTOR has a strong association with breast cancer. Uncontrolled activation of mTOR is shown in a variety of different cancer, making it a critical target for cancer treatment. Inhibition of the mTOR protein kinase can cause autophagic cell death. It is known that covalent inhibitors have become a prominent issue in drug discovery, with covalent inhibitors focusing on α,β-unsaturated carbonyl molecules. Structural modifications to α,β-unsaturated carbonyl may be one of the finest avenues for developing the best breast cancer medication. This review article discusses recent research on natural and synthetic α,β-unsaturated carbonyls and their anti-cancer properties targeting on mTOR, with SAR to showcase the efficacy of synthetic natural products compared to parental compounds using both biological assays and in silico studies

Design and synthesis of a novel mPGES-1 lead inhibitor guided by 3D-QSAR CoMFA

The search of novel mPGES-1 inhibitors has recently intensified probably due to the superior safety in comparison to existing anti-inflammatory drugs. Although two mPGES-1 inhibitors have entered clinical trials, none has yet reached the market. In this study, we performed modifications guided by 3D-QSAR CoMFA on 2, which is an unsymmetrical curcumin derivative with low binding affinity towards mPGES-1. To counter the PAINS properties predicted for 2, the diketone linker was replaced with a pyrazole ring. On the other hand, both prenyl and carboxylate ester groups were introduced to improve the activity. When tested in vitro, 11 suppressed PGE2 biosynthesis in activated macrophages and showed promising human mPGES-1 inhibition in microsomes of interleukin-1β-stimulated A549 cells. Altogether, 11 has been identified as a potential mPGES-1 inhibitor and could be a promising lead for a novel class of mPGES-1 inhibitors