2-Amino Thiazole Derivatives as Prospective Aurora Kinase Inhibitors against Breast Cancer: QSAR, ADMET Prediction, Molecular Docking, and Molecular Dynamic Simulation Studies DOI Creative Commons
B. Sivakumar, Sankaranarayanan Murugesan,

Beutline Malgija

et al.

ACS Omega, Journal Year: 2023, Volume and Issue: 8(46), P. 44287 - 44311

Published: Nov. 7, 2023

The aurora kinase is a key enzyme that implicated in tumor growth. Research revealed small molecules target have beneficial effects as anticancer agents. In the present study, order to identify potential antibreast cancer agents with inhibitory activity, we employed QSARINS software perform quantitative structure-activity relationship (QSAR). statistical values resulted from study include R2 = 0.8902, CCCtr 0.7580, Q2 LOO 0.7875, Q2LMO 0.7624, CCCcv 0.7535, R2ext 0.8735, and CCCext 0.8783. Among four generated models, two best models encompass five important variables, including PSA, EstateVSA5, MoRSEP3, MATSp5, RDFC24. parameters atomic volume, charges, Sanderson's electronegativity played an role designing newer lead compounds. Based on above data, designed six series of compounds 1a-e, 2a-e, 3a-e, 4a-e, 5a-e, 6a-e. All these were subjected molecular docking studies by using AutoDock v4.2.6 against protein (1MQ4). 30 compounds, 2-amino thiazole derivatives 1a, 2a, 3e, 4d, 5d, 6d excellent binding interactions active site 1MQ4. Compound 1a had highest score (-9.67) hence was additionally dynamic simulation investigations for 100 ns. stable compound 1MQ4 verified RMSD, RMSF, RoG, H-bond, mechanics-generalized Born surface area (MM-GBSA), free energy calculations, solvent-accessible (SASA) analyses. Furthermore, newly exhibited ADMET properties. findings, propose may be utilized theoretical future experimental research selective inhibition kinase, therefore assisting creation new drugs.

Language: Английский

Design, synthesis, and SAR studies of novel 4-methoxyphenyl pyrazole and pyrimidine derivatives as potential dual tyrosine kinase inhibitors targeting both EGFR and VEGFR-2 DOI
Abeer M. El‐Naggar,

A.M.A. Hassan,

Eslam B. Elkaeed

et al.

Bioorganic Chemistry, Journal Year: 2022, Volume and Issue: 123, P. 105770 - 105770

Published: April 2, 2022

Language: Английский

Citations

77
Synthesis, structural characterization, DFT calculations, molecular docking, and molecular dynamics simulations of a novel ferrocene derivative to unravel its potential antitumor activity DOI

Mohamed M. Hammoud,

Muhammad Khattab,

Marwa Abdel‐Motaal

et al.

Journal of Biomolecular Structure and Dynamics, Journal Year: 2022, Volume and Issue: unknown, P. 1 - 18

Published: June 8, 2022

In this article, we describe a set of subsequent five-steps chemical reactions to synthesize ferrocene derivative named 1-(5-(diphenylphosphaneyl)cyclopenta-1,3-dien-1-yl)ethyl)imino)-1,3-dihydroisobenzofuran-5-yl)methanol (compound 10). Structural characterization 10 and its intermediate products was also performed reported attest their formation. A molecular docking study propose the novel synthesized (10) as potential antitumor candidate targeting mitogen-activated protein (MAP) kinases interacting kinase (Mnk) 1. The computed score at -9.50 kcal/mol compared native anticancer staurosporine -8.72 postulated promising activity. Also, dynamics (MD) simulations were carried out for 500 ns followed by MM-GBSA-binding free energy calculations both docked complexes give more deep insights into dynamic behavior in physiological conditions. Furthermore, DFT unravel some physiochemical characteristics (10). quantum mechanics shed light on structural electrochemical configurations which would open horizon further investigation. HighlightsThe synthesis 10) described.Structural characterizations performed.DFT calculations, docking, dynamics, MM-GBSA out.Computational studies revealed through inhibiting 1.Communicated Ramaswamy H. Sarma.

Language: Английский

Citations

52
Robust antiviral activity of commonly prescribed antidepressants against emerging coronaviruses: in vitro and in silico drug repurposing studies DOI Creative Commons
Omnia Kutkat, Yassmin Moatasim, Ahmed A. Al‐Karmalawy

et al.

Scientific Reports, Journal Year: 2022, Volume and Issue: 12(1)

Published: July 28, 2022

Abstract During the current coronavirus disease 2019 (COVID-19) pandemic, symptoms of depression are commonly documented among both symptomatic and asymptomatic quarantined COVID-19 patients. Despite that many FDA-approved drugs have been showed anti-SARS-CoV-2 activity in vitro remarkable efficacy against clinical trials, no pharmaceutical products yet declared to be fully effective for treating COVID-19. Antidepressants comprise five major drug classes treatment depression, neuralgia, migraine prophylaxis, eating disorders which frequently reported Herein, eight prescribed antidepressants on inhibition SARS-CoV-2 MERS-CoV was assessed. Additionally, anti-MERS-CoV activities were evaluated. Furthermore, molecular docking studies performed these spike (S) main protease (M pro ) pockets MERS-CoV. Results Amitriptyline, Imipramine, Paroxetine, Sertraline had potential anti-viral activities. Our findings suggested aforementioned deserve more vivo targeting especially those patients suffering from depression.

Language: Английский

Citations

48
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 DOI
Ahmed A. Al‐Karmalawy, Mohamed S. Nafie, Moataz A. Shaldam

et al.

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

Citations

43
Anticoagulants as Potential SARS-CoV-2 Mpro Inhibitors for COVID-19 Patients: In Vitro, Molecular Docking, Molecular Dynamics, DFT, and SAR Studies DOI Open Access
Ayman Abo Elmaaty, Wagdy M. Eldehna, Muhammad Khattab

et al.

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

Citations

42
A Systematic Review of the Global Intervention for SARS-CoV-2 Combating: From Drugs Repurposing to Molnupiravir Approval DOI Creative Commons

Nada A. Ashour,

Ayman Abo Elmaaty,

Amany A. Sarhan

et al.

Drug Design Development and Therapy, Journal Year: 2022, Volume and Issue: Volume 16, P. 685 - 715

Published: March 1, 2022

Abstract: The rising outbreak of SARS-CoV-2 continues to unfold all over the world. development novel effective antiviral drugs fight against is a time cost. As result, some specific FDA-approved have already been repurposed and authorized for COVID-19 treatment. used were either or non-antiviral drugs. Accordingly, present review thoroughly focuses on repurposing efficacy these including clinical trials experienced, combination therapies used, methods followed treatment, their future perspective. Therefore, drug was regarded as an avenue Recently, molnupiravir prodrug medication that approved in United Kingdom November 2021 treatment COVID-19. On other hand, PF-07321332 oral developed by Pfizer. For COVID-19, PF-07321332/ritonavir Phase III studies marketed Paxlovid. Herein, we represented almost history combating from recently available anti-SARS-CoV-2 candidates, new hope end current pandemic. Graphical Keywords: SARS-CoV-2, repurposing, trials, molnupiravir, paxlovid

Language: Английский

Citations

40
Novel 4-thiophenyl-pyrazole, pyridine, and pyrimidine derivatives as potential antitumor candidates targeting both EGFR and VEGFR-2; design, synthesis, biological evaluations, andin silicostudies DOI Creative Commons

Samia M. Al-Muntaser,

Ahmed A. Al‐Karmalawy, Abeer M. El‐Naggar

et al.

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

Citations

29
Metformin ameliorates doxorubicin-induced cardiotoxicity targeting HMGB1/TLR4/NLRP3 signaling pathway in mice DOI
Amany A. Alzokaky, Ahmed A. Al‐Karmalawy, Mohamed A. Saleh

et al.

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

Published: Jan. 14, 2023

Language: Английский

Citations

25
Ligand-based design and synthesis of N'-Benzylidene-3,4-dimethoxybenzohydrazide derivatives as potential antimicrobial agents; evaluation by in vitro, in vivo, and in silico approaches with SAR studies DOI Creative Commons

Rogy R. Ezz Eldin,

Marwa A. Saleh, Mohammad Hayal Alotaibi

et al.

Journal of Enzyme Inhibition and Medicinal Chemistry, Journal Year: 2022, Volume and Issue: 37(1), P. 1098 - 1119

Published: April 18, 2022

Herein, a series of N'-benzylidene-3,4-dimethoxybenzohydrazide derivatives were designed and synthesised to target the multidrug efflux pump (MATE). The antibacterial activities screened against S. aureus, Acinetobacter, typhi, E. coli, P. aeruginosa, whereas their antifungal C. albicans. Compounds 4a, 4h, 4i showed most promising activities. Moreover, compounds 4h being broader superior members regarding antimicrobial effects selected be further evaluated via in vivo testing using biochemical analysis liver/kidney histological examination. Additionally, molecular docking was carried out attain deep insights into compounds' binding modes. Also, ADMET studies performed investigate physicochemical/pharmacokinetics features toxicity parameters derivatives. Finally, structure-antimicrobial activity relationship study established facilitate structural modifications future. HighlightsA new targeting (MATE) guided by pharmacophoric co-crystallized native inhibitor protein.The newly assessed through vitro, vivo, silico approaches.Using agar well diffusion assay, whereas, albicans.The minimal inhibitory concentration (MIC) bactericidal (MBC) investigated on variable microbial species.Compounds (4h 4i) -as effects- bio-chemical examination.A performed.A

Language: Английский

Citations

37
A novel role of Nano selenium and sildenafil on streptozotocin-induced diabetic nephropathy in rats by modulation of inflammatory, oxidative, and apoptotic pathways DOI
Mona F. El-Azab, Ahmed A. Al‐Karmalawy, Samar A. Antar

et al.

Life Sciences, Journal Year: 2022, Volume and Issue: 303, P. 120691 - 120691

Published: June 4, 2022

Language: Английский

Citations

37