Novel Class of Fluorinated Pyrazolo[1,5‐a]pyrimidines as CDK5 and Bcl2 Inhibitors: Design, Synthesis, Biological Evaluation, Molecular Docking and ADME Studies DOI

Mona Said Mohamed,

Zinab Atwa Saad,

Nadia H. Metwally

et al.

ChemistrySelect, Journal Year: 2023, Volume and Issue: 8(34)

Published: Sept. 12, 2023

Abstract New pyrazolo[1,5‐ a ]pyrimidines were designed and synthesized based on the structural analysis of known CDK5 inhibitors. Biological evaluations showed that IC 50 most potent compounds 3 c 5 b targeting normal WI38 (human lung cells) 74.13±4.0 56.19±3.5 μM, respectively safety profile in cells compared to doxorubicin with 6.27±0.5 μM. Compounds , demonstrated inhibitory activity =0.36±0.02 0.226±0.01 roscovitine value 0.149±0.007 Compound also cause significantly increased percentage at phases S by 1.2 fold, untreated cells. It was found downregulation Bcl2 expression 6 folds for than control breast cell. In addition, examination induction apoptosis compound early late apoptotic ratio about 65 66 folds, respectively, proving induces 34.5 %. Moreover, pharmacokinetic properties predicted using ADME calculations, which revealed they inhibit some CYP450 enzymes liver.

Language: Английский

Tumor associated carbonic anhydrase inhibitors: Rational approaches, design strategies, structure activity relationship and mechanistic insights DOI Creative Commons
Sridhar Goud Nerella, Pavitra S. Thacker, Mohammed Arifuddin

et al.

European Journal of Medicinal Chemistry Reports, Journal Year: 2024, Volume and Issue: 10, P. 100131 - 100131

Published: Jan. 18, 2024

The emergence of tumor-associated human carbonic anhydrases (hCA) as promising therapeutic targets has urged rigorous research into the development potent and selective hCA IX XII inhibitors. Rationalization targeting tumor-specific isoforms is a major challenge that requires comprehensive understanding interactions between inhibitors dynamic active site. benzenesulfonamides its bioisosteres are currently being used clinically various through classical inhibitory mechanism. In addition, several other chemotypes have also been developed with improved potency selectivity non-classical mechanisms. Coumarin derivatives represent highly XII. Recently, pharmacophores were proven to strong against including pyrazole, 1,2,3-triazole, 4-thiazolidinone, thiourea. This review navigates role in cancer biology, encompassing different inhibition approaches, strategic design methodologies, recent advancements rational inhibitors, exploration structure-activity relationships, in-depth mechanistic insights, PET imaging applications for vivo visualization target enzymes.

Language: Английский

Citations

13
Identification of thienopyrimidine derivatives tethered with sulfonamide and other moieties as carbonic anhydrase inhibitors: Design, synthesis and anti-proliferative activity DOI

Samah Higazy,

Nermin Samir,

Ahmed El‐Khouly

et al.

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 144, P. 107089 - 107089

Published: Jan. 12, 2024

Language: Английский

Citations

12
Synthesis of new sulfonamide derivatives: Investigation of their interactions with carbonic anhydrase and cholinesterase enzymes by in vitro and in silico evaluations DOI
Muhammet Gürkan Kurban, Reşit Çakmak, Eyüp Başaran

et al.

Journal of Molecular Structure, Journal Year: 2024, Volume and Issue: 1314, P. 138798 - 138798

Published: May 30, 2024

Language: Английский

Citations

8
Synergistic and potential antifungal properties of tailored, one pot multicomponent monoterpenes co-delivered with fluconazole encapsulated nanostructure lipid carrier DOI Creative Commons
Ibrahim Taha Radwan, Ibrahim M. El‐Sherbiny, Nadia H. Metwally

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: June 22, 2024

Frequent and variant infections are caused by the virtue of opportunistic fungi pathogens. Candidiasis, aspergillosis, mucormycosis pathogenic microorganisms that give rise to vast fungal diseases alternate between moderate fatal in severity. The use fluconazole as an antifungal drug was limited due acquired resistance some types Candida other species. This study aims consolidate fluconazole's biological effectiveness against several fungi. Six active monoterpenes (MTs) carvacrol, linalool, geraniol, α-terpinene, citronellal, nerolidol were selected encapsulated nanostructure lipid carrier (NLC) with (NLC-Flu-MTs) and/without (NLC-MTs) one nanoformulation determine if they will act synergistically or not? synthesized NLC-Flu-MTs NLC-MTs exhibited very good particle size 144.5 nm 138.6 for zeta potential values (- 23.5 mV) 20.3 mV), respectively. Transmission electron microscope investigation confirmed NLCs have regular spherical shape. abundance concentration six released determined, a novel approach, using GC-MS results validity. In-vitro screening done before after nano co-delivery seven pathogenic, aggressive tropicalis, krusei, glabrata, Geotrichum Candidum, Candidaalbicans, Aspergillus Niger, mucor circinelloides. Inhibition Zone diameter (IZD) minimum inhibitory (MIC) measured. Nanoformulations manifested unique susceptibility all tested reduced values, especially Tropicalis (MIC = 0.97 µg/ml) which represents 16-fold value shown 15.6 64-fold free 62.5 µg/ml). efficiency nanomaterials, particularly NLC-Flu-MTs, has become evident diminishing MIC affirmed synergism monoterpenes.

Language: Английский

Citations

6
Synthesis, anticancer evaluation, molecular docking and ADME study of novel pyrido[4ʹ,3ʹ:3,4]pyrazolo[1,5-a]pyrimidines as potential tropomyosin receptor kinase A (TrKA) inhibitors DOI Creative Commons
Nadia H. Metwally,

Emad Abdullah Deeb,

Ibrahim Walid Hasani

et al.

BMC Chemistry, Journal Year: 2024, Volume and Issue: 18(1)

Published: April 6, 2024

Abstract The starting compound 3-amino-1,7-dihydro-4 H -pyrazolo[4,3- c ]pyridine-4,6(5 )-dione (1) is reacted with each of diketone and β -ketoester, forming pyridopyrazolo[1,5- a ]pyrimidines 4a , b 14a respectively. compounds 4 14 aromatic aldehyde arenediazonium salt to give the respective arylidenes arylhydrazo derivatives, structure new products was established using spectroscopic techniques. cytotoxic activity selected targets tested in vitro against three cancer cell lines MCF7 HepG2 HCT116 . data obtained from enzymatic assays TrKA indicated that 7b 16c have strongest inhibitory effects on IC 50 = 0.064 ± 0.0037 μg/ml 0.047 0.0027 μg/ml, respectively, compared standard drug Larotrectinib 0.034 0.0021 for line. In cycle analysis, 15b 16a caused greatest arrest at G2/M phase. addition, has higher apoptosis-inducing effect (36.72%) than (34.70%), (21.14) (26.54%). Compounds were shown fit tightly into active site kinase crystal (PDB: 5H3Q). Also, ADME study performed some potent anticancer described this study.

Language: Английский

Citations

5
Knoevenagel-IMHDA and -IMSDA sequences for the synthesis of chiral condensed O,N-, S,N- and N-heterocycles DOI Creative Commons

Mihály Kajtár,

Sándor Balázs Király, Attila Bényei

et al.

RSC Advances, Journal Year: 2025, Volume and Issue: 15(2), P. 1230 - 1248

Published: Jan. 1, 2025

Heterocycles containing hexahydrobenzo[ j ]phenanthridine and hexahydro-1 H -(thio)pyrano[3,4- c ]pyridine skeletons were prepared by domino Knoevenagel-styryl Diels–Alder intramolecular hetero-Diels–Alder sequences, respectively.

Language: Английский

Citations

0
Chemistry of heterocycles as carbonic anhydrase inhibitors: A pathway to novel research in medicinal chemistry review DOI
Anjaneyulu Bendi,

Taruna,

Rajni Rajni

et al.

Archiv der Pharmazie, Journal Year: 2024, Volume and Issue: 357(7)

Published: April 29, 2024

Abstract Nowadays, the scientific community has focused on dealing with different kinds of diseases by exploring chemistry various heterocycles as novel drugs. In this connection, medicinal chemists identified carbonic anhydrases (CA) one biologically active targets for curing diseases. The widespread distribution these enzymes and high degree homology shared isoforms offer substantial challenges to discovering potential Medicinal synthetic organic have been continuously involved in developing CA inhibitors. This review explored inhibitors using last 11 years published research work. It provides a pathway young researchers further explore variety well natural

Language: Английский

Citations

3
Juglone-Bearing Thiopyrano[2,3-d]thiazoles Induce Apoptosis in Colorectal Adenocarcinoma Cells DOI Creative Commons
Yuliia Kozak, Nataliya Finiuk, Robert Czarnomysy

et al.

Cells, Journal Year: 2025, Volume and Issue: 14(6), P. 465 - 465

Published: March 20, 2025

Colorectal cancer is a major global health challenge, with current treatments limited by toxicity and resistance. Thiazole derivatives, known for their bioactivity, are emerging as promising alternatives. Juglone (5-hydroxy-1,4-naphthoquinone) naturally occurring compound anticancer properties, its incorporation into thiopyrano[2,3-d]thiazole scaffolds may enhance therapeutic potential. This study examined the cytotoxicity of thiopyrano[2,3-d]thiazoles effects on apoptosis in colorectal cells. Les-6547 Les-6557 increased population ROS-positive HT-29 cells approximately 10-fold compared control (36.3% 38.5% vs. 3.8%, respectively), potentially contributing to various downstream effects. Elevated ROS levels were associated cell cycle arrest, inhibition DNA biosynthesis, reduced proliferation. A significant shift distribution was observed, an increase S-phase (from 17.3% 34.7% 51.3% Les-6557, respectively) G2/M phase 24.3% 39.9% 28.8%). Additionally, inhibited biosynthesis cells, IC50 values 2.21 µM 2.91 µM, respectively. generation initiate intrinsic apoptotic pathway. activated both extrinsic pathways, demonstrated notable increases activity caspase 3/7, 8, 9, 10. provides robust basis investigating detailed molecular mechanisms action potential Les-6557.

Language: Английский

Citations

0
Update on Thiopyran Fused Heterocycle Synthesis (2013-2024) DOI
Ani Deepthi,

Sruthi Sudheendran Leena,

Devika Krishnan

et al.

Organic & Biomolecular Chemistry, Journal Year: 2024, Volume and Issue: 22(28), P. 5676 - 5717

Published: Jan. 1, 2024

Thiopyrans and their fused derivatives have significant synthetic relevance owing to biological importance occurrence in natural products. The current article provides an overview of strategies employed for the construction thiopyran-fused heterocycles. In particular, this discusses methods fusion thiopyran with heterocycles such as indole, quinoline, pyrimidine, pyridine, thiophene, chromene, oxazole, pyrazole, pyran furan covers literature from 2013 2024. most common precursors thiopyrano[2,3-

Language: Английский

Citations

2
Design, synthesis of some novel coumarins and their nanoformulations into lipid-chitosan nanocapsule as unique antimicrobial agents DOI Creative Commons
Ibrahim Taha Radwan, Ibrahim M. El‐Sherbiny, Abdelfattah Selim

et al.

Scientific Reports, Journal Year: 2024, Volume and Issue: 14(1)

Published: Dec. 23, 2024

Abstract Developing and creating novel antibiotics is one of the most important targets in treating infectious diseases. Novel coumarins were synthesized characterized using different spectroscopic techniques such as Fourier Transform Infrared (FTIR), Nuclear magnetic resonance 1 H 13 C mass spectroscopy (MS). All compounds have been tested for activity sensitivity against microbial strains B. subtilis , S. aureus E. coli P. aeruginosa typhi C. albicans . showed substantial results microbes except which was not affected any way by these coumarins. Exceptional shown 4 6d 8b made them best candidates loading to vicinity nanostructure lipid carrier coated chitosan nanocapsule (NLC-Cs). Transmission electron microscope (TEM) confirmed spherical morphology with particles size less than 500 nm. Also, dynamic light scattering (DLS) utilized measure average particle (between 100 200 nm) stability assessed zeta potential found be more positive confirming encapsulation. Antimicrobial assessments performed both synthetic their NLCs analogues. The nanoformulation -NLC-Cs, -NLC-Cs manifested unique biological results, especially revealed powerful effects over all organisms including increasing effect drugs nanoscale form reflected value inhibition zone diameter suppressing MIC reach record levels like disclosed = 0.48 0.24 µg/ml respectively, mean suppressed 65 folds its initial before nano. In continuation, it proven that make noticeable changes on DNA-Gyrase reduced IC 50 values particularly excellent inhibitory 4.56 µM. TEM used pursue morphological occur bacterial cells weakness cell wall treated nanomaterials, has reached point rupture components spilling out causing necrotic death.

Language: Английский

Citations

2