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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Ligand-Based Design on the Dog-Bone-Shaped BIBR1532 Pharmacophoric Features and Synthesis of Novel Analogues as Promising Telomerase Inhibitors with In Vitro and In Vivo Evaluations

Journal of Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 66(1), P. 777 - 792

Published: Dec. 16, 2022

Telomerase is an outstanding biological target for cancer treatment. BIBR1532 a non-nucleoside selective telomerase inhibitor; however, it experiences ineligible pharmacokinetics. Herein, we aimed to design new BIBR1532-based analogues as promising inhibitors. Therefore, two novel series of pyridazine-linked cyclopenta[b]thiophene (8a-f) and tetrahydro-1-benzothiophene (9a-f) were synthesized. A quantitative real-time polymerase chain reaction was utilized investigate the inhibitory activity candidates. Notably, 8e 9e exhibited best inhibition profiles. Moreover, showed strong antitumor effects against both MCF-7 A549 cell lines. The on cycle apoptosis measured. Besides, evaluated its in vivo using solid Ehrlich carcinoma. reduction tumor weight volume greater than doxorubicin. Also, molecular docking ADME studies performed. Finally, SAR study conducted gain further insights into different potentials upon variable structural modifications.

Language: Английский

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Anticoagulants as Potential SARS-CoV-2 Mpro Inhibitors for COVID-19 Patients: In Vitro, Molecular Docking, Molecular Dynamics, DFT, and SAR Studies

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(20), P. 12235 - 12235

Published: Oct. 13, 2022

In this article, 34 anticoagulant drugs were screened in silico against the main protease (Mpro) of SARS-CoV-2 using molecular docking tools. Idraparinux, fondaparinux, eptifibatide, heparin, and ticagrelor demonstrated highest binding affinities towards Mpro. A dynamics study at 200 ns was also carried out for most promising anticoagulants to provide insights into dynamic thermodynamic properties compounds. Moreover, a quantum mechanical conducted which helped us attest some findings. biological evaluation (in vitro) compounds performed by carrying MTT cytotoxicity assay crystal violet order assess inhibitory concentration 50 (IC50). It is worth noting that displayed intrinsic potential inhibition with an IC50 value 5.60 µM safety index 25.33. addition, fondaparinux sodium dabigatran showed activities values 8.60 9.40 µM, respectively, indexes 17.60 15.10, respectively. Mpro enzyme investigated utilizing tipranavir as reference standard. Interestingly, attained 2.36 surpassing (IC50 = 7.38 µM) more than three-fold. Furthermore, highly eligible 10.59 µM. Finally, SAR discussed, counting on findings both vitro approaches.

Language: Английский

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In vitroand computational investigations of novel synthetic carboxamide-linked pyridopyrrolopyrimidines with potent activity as SARS-CoV-2-M^Proinhibitors

RSC Advances, Journal Year: 2022, Volume and Issue: 12(41), P. 26895 - 26907

Published: Jan. 1, 2022

An essential target for COVID-19 is the main protease of SARS-CoV-2 (Mpro). With objective targeting this receptor, a novel set pyrido[1,2-a]pyrrolo[2,3-d]pyrimidines with terminal carboxamide fragments was designed, synthesized, and considered as an initial motif creation effective pan-coronavirus inhibitors. Accordingly, nine derivatives (21-29) have been introduced in vitro assay to evaluate their antiviral activity cytotoxicity effect against virus using Vero cells. The obtained data revealed that majority these showed potent cellular anti-COVID-19 prevent viral growth by more than 90% at two different concentrations weak or even no detectable cytotoxic on Extensive molecular docking simulations highlighted proper non-covalent interaction new compounds within binding pocket Mpro potential activity. In all synthesized indicated 25 29 promising inhibitory IC50 values low micromolar concentrations. dynamic simulation results predicted stability compound cavity hence supported high shown assay. These suggested merit further investigations drug candidates management SARS-CoV-2.

Language: Английский

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Phenylpyrazolone-1,2,3-triazole Hybrids as Potent Antiviral Agents with Promising SARS-CoV-2 Main Protease Inhibition Potential

Pharmaceuticals, Journal Year: 2023, Volume and Issue: 16(3), P. 463 - 463

Published: March 20, 2023

COVID-19 infection is now considered one of the leading causes human death. As an attempt towards discovery novel medications for pandemic, nineteen compounds containing 1,2,3-triazole side chains linked to phenylpyrazolone scaffold and terminal lipophilic aryl parts with prominent substituent functionalities were designed synthesized via a click reaction based on our previous work. The assessed using in vitro effect growth SARS-CoV-2 virus-infested Vero cells different compound concentrations: 1 10 μM. data revealed that most these derivatives showed potent cellular anti-COVID-19 activity inhibited viral replication by more than 50% no or weak cytotoxic harboring cells. In addition, assay employing SARS-CoV-2-Main protease inhibition was done test inhibitors' ability block common primary virus as mode action. obtained results show non-linker analog 6h two amide-based linkers 6i 6q active IC50 values 5.08, 3.16, 7.55 μM, respectively, against comparison selective antiviral agent GC-376. Molecular modeling studies placement within binding pocket which reveal conserved residues hydrogen bonding non-hydrogen interactions fragments: triazole scaffold, part, linker. Moreover, stability their target also studied analyzed molecular dynamic simulations. physicochemical toxicity profiles predicted, behave low organ toxicity. All research point potential usage new chemotype promising leads be explored vivo might open door rational drug development Main medicines.

Language: Английский

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Design and synthesis of novel benzoazoninone derivatives as potential CBSIs and apoptotic inducers: In Vitro, in Vivo, molecular docking, molecular dynamics, and SAR studies

Bioorganic Chemistry, Journal Year: 2022, Volume and Issue: 127, P. 105995 - 105995

Published: June 30, 2022

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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Exploring the cytotoxic effect and CDK-9 inhibition potential of novel sulfaguanidine-based azopyrazolidine-3,5-diones and 3,5-diaminoazopyrazoles

Bioorganic Chemistry, Journal Year: 2023, Volume and Issue: 133, P. 106397 - 106397

Published: Feb. 1, 2023

Language: Английский

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Design, synthesis, and mechanistic insight of novel imidazolones as potential EGFR inhibitors and apoptosis inducers

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 144, P. 107105 - 107105

Published: Jan. 8, 2024

Language: Английский

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