Synthesis of New Organoselenium-Based Succinanilic and Maleanilic Derivatives and In Silico Studies as Possible SARS-CoV-2 Main Protease Inhibitors

Inorganics, Journal Year: 2023, Volume and Issue: 11(8), P. 321 - 321

Published: July 29, 2023

Herein we report the synthesis of organic selenide-based maleanilic and succinanilic acids in good yields (up to 95%). Their structural identities were elucidated by spectroscopic techniques (e.g., IR, 1H- & 13C-NMR, MS). The ADMET analysis, molecule electrostatic potential map, DFT, frontier molecular orbital used study organoselenium compounds’ pharmacokinetics, drug-likeness characteristics, geometries, chemical electronic properties. Moreover, a docking tool was employed investigate selenides’ ability inhibit SARS-CoV-2 Mpro target (PDB: 7BFB). Within this context, selenides exhibited promising binding affinities receptor following order (12 > 11 10 9 7 8). Furthermore, dynamics simulations also carried out for 200 ns evaluate exact behavior most active compound (12) within pocket compared with its co-crystallized inhibitor (Co).

Language: Английский

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Design, synthesis, and molecular dynamics-driven evaluation of quinoline-sulfonamide derivatives as potent and selective EGFR inhibitors with promising anti-cancer efficacy and safety profiles

Bioorganic Chemistry, Journal Year: 2025, Volume and Issue: unknown, P. 108247 - 108247

Published: Feb. 1, 2025

Language: Английский

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Design, synthesis and biological evaluation of pyrazolo[3,4- b ]pyridine derivatives as dual CDK2/PIM1 inhibitors with potent anti-cancer activity and selectivity

Journal of Biomolecular Structure and Dynamics, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 25

Published: March 13, 2025

The discovery of novel, selective inhibitors targeting CDK2 and PIM1 kinases, which regulate cell survival, proliferation, treatment resistance, is crucial for advancing cancer therapy. This study reports the design, synthesis, biological evaluation three novel pyrazolo[3,4-b]pyridine derivatives (6a-c), confirmed via spectral analyses. These compounds were assessed anti-cancer activity against breast, colon, liver, cervical cancers using MTT assay. Among tested compounds, 6b exhibited superior efficacy, with higher selectivity indices HCT-116 (15.05) HepG2 (9.88) compared to reference drug staurosporine. Mechanistic studies revealed that induced apoptosis (63.04-fold increase) arrested cycle at G0-G1 phase, highlighting its anti-proliferative effects. In an in-vivo solid Ehrlich carcinoma (SEC) mouse model, compound significantly reduced tumor weight volume, exceeding efficacy doxorubicin. Additionally, potently inhibited kinases (IC50: 0.27 0.67 µM, respectively) tumor-promoting TNF-alpha expression, as by histopathological immunohistochemical studies. Computational analyses, including molecular docking, dynamics simulations, DFT calculations, provided insights into binding stability interaction mechanisms PIM1, while in-silico pharmacokinetic toxicity evaluations favorable drug-like profile safety. highlights a promising dual CDK2/PIM1 inhibitor potent selectivity, paving way further optimization development lead molecule in

Language: Английский

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Novel 4-thiophenyl-pyrazole, pyridine, and pyrimidine derivatives as potential antitumor candidates targeting both EGFR and VEGFR-2; design, synthesis, biological evaluations, andin silicostudies

RSC Advances, Journal Year: 2023, Volume and Issue: 13(18), P. 12184 - 12203

Published: Jan. 1, 2023

In this article, we continued our previous effort to develop new selective anticancer candidates based on the basic pharmacophoric requirements of both EGFR and VEGFR-2 inhibitors. Therefore, twenty-two novel 4-thiophenyl-pyrazole, pyridine, pyrimidine derivatives were designed examined as dual EGFR/VEGFR-2 Besides, previously reported antimicrobial activities aforementioned nuclei motivated us screen their antibacterial antifungal well. First, antitumor newly synthesized evaluated against two cancer cell lines (HepG-2 MCF-7). Notably, compounds 2a, 6a, 7a, 10b, 15a, 18a exhibited superior HepG-2 MCF-7 lines. These selected further evaluate anti-EGFR anti-VEGFR-2 potentialities which found be very promising compared erlotinib sorafenib, respectively. Both 10b 2a achieved better inhibition with IC50 values 0.161 0.141 μM 0.209 0.195 μM, Moreover, most active was exact phase cycle arrest investigate mechanism death whether it due apoptosis or necrosis. On other hand, all tested Gram-positive bacteria such S. aureus B. subtilis well Gram-negative E. coli P. aeuroginosa. Also, activity investigated C. albicans A. flavus strains. The findings tests revealed that strong moderate effects. Furthermore, understand pattern by bound site, subjected different docking processes into binding sites. tried correlate compound reference drugs (erlotinib sorafenib) through DFT calculations. Finally, following biological data pyrazole, candidates, concluded a interesting SAR for optimization.

Language: Английский

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Metformin ameliorates doxorubicin-induced cardiotoxicity targeting HMGB1/TLR4/NLRP3 signaling pathway in mice

Life Sciences, Journal Year: 2023, Volume and Issue: 316, P. 121390 - 121390

Published: Jan. 14, 2023

Language: Английский

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Some pyrimidohexahydroquinoline candidates: synthesis, DFT, cytotoxic activity evaluation, molecular docking, and in silico studies

RSC Advances, Journal Year: 2024, Volume and Issue: 14(23), P. 16584 - 16599

Published: Jan. 1, 2024

Hexahydroquinolines were prepared and supported by in silico studies. Thiosemicarbazide thiazolidinone derivatives showed the highest vitro antiproliferative potency against liver, breast, prostate, colon cancer cell lines.

Language: Английский

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Phytochemical investigation, role in wound healing process and cytotoxicity of Sphagneticola trilobata: In vitro, in vivo and in silico approach.

Journal of Ethnopharmacology, Journal Year: 2025, Volume and Issue: unknown, P. 119394 - 119394

Published: Jan. 1, 2025

Language: Английский

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Medicinal chemistry strategies towards the development of non-covalent SARS-CoV-2 Mpro inhibitors

Acta Pharmaceutica Sinica B, Journal Year: 2023, Volume and Issue: 14(1), P. 87 - 109

Published: Aug. 9, 2023

The main protease (Mpro) of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role the virus life cycle. covalent Mpro inhibitor nirmatrelvir (in combination with ritonavir, a pharmacokinetic enhancer) non-covalent ensitrelvir have shown efficacy clinical trials been approved therapeutic use. Effective antiviral drugs are needed to fight pandemic, while inhibitors could be promising alternatives due their selectivity favorable druggability. Numerous desirable properties developed based on available crystal structures Mpro. In this article, we describe medicinal chemistry strategies applied discovery optimization inhibitors, followed by general overview critical analysis information. Prospective viewpoints insights into current development also discussed.

Language: Английский

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Design, synthesis, and biological evaluation of thienopyrimidine derivatives as multifunctional agents against Alzheimer's disease

Drug Development Research, Journal Year: 2023, Volume and Issue: 84(5), P. 937 - 961

Published: April 17, 2023

A series of 12 S-substituted tetrahydrobenzothienopyrimidines were designed and synthesized based on the donepezil scaffold. All newly compounds evaluated for their acetylcholinesterase (AChE) inhibitory activity most active tested butyrylcholinesterase (BuChE) activity. Moreover, all effects against Aβ aggregation antioxidant using oxygen radical absorbance capacity method. Compounds 4b, 6b, 8b displayed prominent AChE action comparable to donepezil. Compound 6b showed greatest (IC50 = 0.07 ± 0.003 µM) potent BuChE 0.059 0.004 µM). Furthermore, three exhibited significant exerted more than The cytotoxic WI-38 cell line in comparison with was examined 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide assay. results revealed that less cytotixic donepezil, while compound 4b nonsignificant cytotoxicity compared For insights about binding patterns promising (4b, 8b) at molecular levels; docking dynamics simulations performed. density functional theory calculations absorption, distribution, metabolism, excretion toxicity properties described as well. highlighted which incorporates a phenylpiperazine moiety coupled thienopyrimidone scaffold via two-atom spacer, be multifunctional therapeutic agent treatment Alzheimer's disease. It is dual inhibitor. it had stronger Additionally,

Language: Английский

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Identification of sulphonamide-tethered N -((triazol-4-yl)methyl)isatin derivatives as inhibitors of SARS-CoV-2 main protease

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 38(1)

Published: July 11, 2023

SARS-CoV-2 pandemic in the end of 2019 led to profound consequences on global health and economy. Till producing successful vaccination strategies, healthcare sectors suffered from lack effective therapeutic agents that could control spread infection. Thus, academia pharmaceutical sector prioritise antiviral drug discovery. Here, we exploited previous reports highlighting anti-SARS-CoV-2 activities isatin-based molecules develop novel triazolo-isatins for inhibiting main protease (Mpro) virus, a crucial enzyme its replication host cells. Particularly, sulphonamide 6b showed promising inhibitory activity with an IC50= 0.249 µM. Additionally, inhibited viral cell proliferation IC50 4.33 µg/ml, was non-toxic VERO-E6 cells (CC50 = 564.74 µg/ml) displaying selectivity index 130.4. In silico analysis disclosed ability interact key residues active site, supporting obtained vitro findings.

Language: Английский

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