The anticancer and EGFR-TK/CDK-9 dual inhibitory potentials of new synthetic pyranopyrazole and pyrazolone derivatives: X-ray crystallography, in vitro , and in silico mechanistic investigations

Journal of Biomolecular Structure and Dynamics, Год журнала: 2023, Номер 41(21), С. 12411 - 12425

Опубликована: Янв. 20, 2023

Treatment options for the management of breast cancer are still inadequate. This inadequacy is attributed to lack effective targeted medications, often resulting in recurrence metastatic disorders. Cumulative evidence suggests that epidermal growth factor receptor (EGFR-TK) and cyclin-dependent kinases-9 (CDK-9) overexpression correlates with worse overall survival patients. Pyranopyrazole pyrazolone privileged development anticancer agents. Inspired by this proven scientific fact, we report here synthesis two new series suggested molecules incorporating both heterocycles together their characterization IR, 1H NMR, 13C NMR-DEPT, X-ray diffraction methods. An attempt get pyranopyrazole-gold complexes was conducted but unexpectedly yielded benzylidene-2,4-dihydro-3H-pyrazol-3-one instead. unexpected result confirmed crystallographic analysis. All newly synthesized compounds were assessed anti-proliferative activity against different human cells, obtained results compared reference drug Staurosporine. The target revealed variable cytotoxicity IC50 at a low micromolar range superior selectivity indices. Target enzyme EGFR-TK CDK-9 assays showed 22 23 effectively inhibited biological targets values 0.143 0.121 µM, respectively. Molecular docking experiments molecular dynamics simulation also further rationalize vitro results.Communicated Ramaswamy H. Sarma.

Язык: Английский

---

Chalcones and Gastrointestinal Cancers: Experimental Evidence

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(6), С. 5964 - 5964

Опубликована: Март 22, 2023

Colorectal (CRC) and gastric cancers (GC) are the most common digestive tract with a high incidence rate worldwide. The current treatment including surgery, chemotherapy or radiotherapy has several limitations such as drug toxicity, cancer recurrence resistance thus it is great challenge to discover an effective safe therapy for CRC GC. In last decade, numerous phytochemicals their synthetic analogs have attracted attention due anticancer effect low organ toxicity. Chalcones, plant-derived polyphenols, received marked biological activities well relatively easy structural manipulation synthesis of new chalcone derivatives. this study, we discuss mechanisms by which chalcones in both vitro vivo conditions suppress cell proliferation formation.

Язык: Английский

---

A novel class of phenylpyrazolone-sulphonamides rigid synthetic anticancer molecules selectively inhibit the isoform IX of carbonic anhydrases guided by molecular docking and orbital analyses

Journal of Biomolecular Structure and Dynamics, Год журнала: 2023, Номер 41(24), С. 15243 - 15261

Опубликована: Март 13, 2023

All the previously reported phenylpyrazoles as carbonic anhydrase inhibitors (CAIs) were found to have small sizes and high levels of flexibility, hence showed low selectivity profiles toward a particular isoform CA. Herein, we report development more rigid ring system bearing sulfonamide hydrophilic head lipophilic tail develop novel molecules that are suggested better special CA isoform. Accordingly, three sets pyrano[2,3-c]pyrazoles attached with aryl hydrophobic synthesized enhance specific human anhydrases (hCAs). The impact both attachments on potency has been extensively discussed in terms vitro cytotoxicity evaluation under hypoxic conditions, structure-activity relationship enzyme assay. new candidates displayed good cytotoxic activities against breast colorectal carcinomas. Results assay demonstrated preferential compounds 22, 24 27 inhibit IX hCAs selectively. Wound-healing also performed revealed potential decrease wound closure percentage MCF-7 cells. Molecular docking molecular orbital analysis finally conducted. indicate binding interactions several crucial amino acids hCA IX.Communicated by Ramaswamy H. Sarma.

Язык: Английский

---

Discovery of gefitinib-1,2,3-triazole derivatives against lung cancer via inducing apoptosis and inhibiting the colony formation

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Апрель 22, 2024

Abstract A series of 20 novel gefitinib derivatives incorporating the 1,2,3-triazole moiety were designed and synthesized. The synthesized compounds evaluated for their potential anticancer activity against EGFR wild-type human non-small cell lung cancer cells (NCI-H1299, A549) adenocarcinoma (NCI-H1437) as cancer. In comparison to gefitinib, Initial biological assessments revealed that several exhibited potent anti-proliferative these lines. Notably, 7a 7j demonstrated most pronounced effects, with an IC 50 value 3.94 ± 0.17 µmol L −1 (NCI-H1299), 3.16 0.11 (A549), 1.83 0.13 , 3.84 0.22 3.86 0.38 1.69 0.25 . These two could inhibit colony formation migration ability H1299 cells, induce apoptosis in cells. Acute toxicity experiments on mice compound low mice. Based results, it is proposed potentially be developed drugs treatment

Язык: Английский

---

Design, synthesis, cytotoxic activities, and molecular docking of chalcone hybrids bearing 8-hydroxyquinoline moiety with dual tubulin/EGFR kinase inhibition

Bioorganic Chemistry, Год журнала: 2023, Номер 134, С. 106444 - 106444

Опубликована: Фев. 25, 2023

Язык: Английский

---

Recent advances in chalcone-triazole hybrids as potential pharmacological agents

Results in Chemistry, Год журнала: 2023, Номер 6, С. 101173 - 101173

Опубликована: Окт. 20, 2023

Molecular hybridization is one of the recent strategies to synthesize a novel hybrid compound by combining two or more pharmacophoric units. Being linkage process, it focuses on synthesis hybrids which are less toxic and potent than their parent Therefore, nowadays medicinal chemists look forwards for new drugs using molecular hybridization. Chalcones class very important structural motifs in chemistry. Similarly, 1,2,3-triazoles heterocyclic bio-isostere having vast spectrum applications due its ease synthesis, hydrogen bond formation capacity, inertness towards oxidizing reducing agents, moderate dipole moment good binding with several agents. In this review, we have summarized research articles describing application synthetic chalcone-triazoles derivatives. The structural-activity relationship has been discussed may provide helpful guidelines future drug based chalcone triazole moieties.

Язык: Английский

---

New 1,2,3-triazole/1,2,4-triazole hybrids linked to oxime moiety as nitric oxide donor selective COX-2, aromatase, B-RAF ^V600E and EGFR inhibitors celecoxib analogs: design, synthesis, anti-inflammatory/anti-proliferative activities, apoptosis and molecular modeling study

Journal of Enzyme Inhibition and Medicinal Chemistry, Год журнала: 2023, Номер 38(1)

Опубликована: Дек. 7, 2023

A new series of bis-triazole 19a-l was synthesised for the purpose being hybrid molecules with both anti-inflammatory and anti-cancer activities assessed cell cycle arrest, NO release. Compounds 19c, 19f, 19h, 19 l exhibited COX-2 selectivity indexes in range 18.48 to 49.38 compared celecoxib S.I. = 21.10), inhibit MCF-7 IC50 9–16 μM tamoxifen (IC50 27.9 μM). showed good inhibitory activity against HEP-3B 4.5–14 sorafenib 3.5 μM) (HEP-3B). Moreover, derivatives 19e, 19j, 19k, HCT-116 5.3–13.7 5-FU 4.8 (HCT-116). excellent A549 3–4.5 6 (A549). aromatase 22.40, 23.20, 22.70, 30.30 μM), EGFR 0.112, 0.205, 0.169 0.066 B-RAFV600E 0.09, 0.06, 0.07 0.05

Язык: Английский

---

Novel fluorinated pyrazole-based heterocycles scaffold: cytotoxicity, in silico studies and molecular modelling targeting double mutant EGFR L858R/T790M as antiproliferative and apoptotic agents

Medicinal Chemistry Research, Год журнала: 2023, Номер 32(2), С. 369 - 388

Опубликована: Янв. 2, 2023

Abstract Hepatocellular carcinoma (HCC), also known as hepatoma, is the most prevalent type of primary liver cancer. It begins in hepatocytes, liver’s major cell type. Cancer that began another region body but has spread to secondary cancer life; several still unmet demands for better, less toxic therapy treat this malignant tumor. Several novel pyrazolo[1,5- a ]pyrimidine derivatives were synthesized part our goal develop promising anticancer drugs. All hybrids have been screened their cytotoxicity effect against three lines which are; HepG-2, HCT-116, and MCF-7. The cells found be sensitive new molecules. A subsequent set vitro biological evaluation studies conducted on identify such In HepG-2 cells, four ( 8a , 8b 10c 11b ) demonstrated good activity. efficacious compounds had IC 50 values 2.36 ± 0.14 1.14 0.063 μM, respectively, higher than reference medication Imatinib. latter’s putative molecular investigated further by looking at its influence cycle, EGFR, specific apoptotic anti-apoptotic markers cells. These findings indicated could trigger apoptosis upregulating BAX caspase-3 cycle Pre-G1 G2-M stages. showed high potency EGFR with equal 0.098 0.079 respectively. Compound effective inhibitory activity L858R-TK (36.79 nM). Additionally, silico ADMET docking done active hits, representing results. Graphical

Язык: Английский

---

Structure-based development of 3,5-dihydroxybenzoyl-hydrazineylidene as tyrosinase inhibitor; in vitro and in silico study

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Янв. 17, 2024

Abstract A series of new analogs 3,5-dihydroxybenzoyl-hydrazineylidene conjugated to different methoxyphenyl triazole ( 11a-n ) synthesized using click reaction. The structures all compounds were characterized by FTIR, 1 H, 13 C-NMR spectroscopy, and CHO analysis. tyrosinase inhibitory potential the was studied. newly scaffolds found illustrate variable degree profile, most potent analog this that one bearing 4-methoxyphenyl moiety, exhibited an IC 50 value 55.39 ± 4.93 µM. kinetic study derivative reveals a competitive mode inhibition. Next, molecular docking studies performed understand inhibitor's binding within enzyme's site. Molecular dynamics simulations accomplished further investigate orientation interaction over time stability 11m -tyrosinase complex.

Язык: Английский

---

Therapeutic potential of chalcone-1,2,3-triazole hybrids as anti-tumour agents: a systematic review and SAR studies

Future Medicinal Chemistry, Год журнала: 2025, Номер 17(4), С. 449 - 465

Опубликована: Янв. 31, 2025

The study of chalcone-1,2,3-triazole hybrids for anticancer activity is quite a recent area focus, primarily because the increasing demand developing new drugs to treat cancer. chalcones and 1,2,3-triazole rings in hybrid compounds has recently emerged as promising strategy novel agents. ring, known its stability hydrogen bonding capabilities, enhances target binding affinity these hybrids. Chalcones possess an α,β-unsaturated carbonyl system crucial their synergistic effect two moieties results with potent properties. This review explores structure-activity relationship studies which revealed that electronic lipophilic properties substituents on phenyl significantly influence activity. Electron-donating electron-withdrawing groups can affect cellular uptake engagement. Incorporating various into ring improve selectivity potency against specific cancer cell lines. These often exert effects through apoptosis cycle disruption. Recent research indicates chalcone hold therapeutic promise Further optimization SAR in-depth mechanistic investigations could lead development highly selective agents minimal toxicity.

Язык: Английский

---