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Synthesis, antimicrobial, molecular docking and molecular dynamics studies of lauroyl thymidine analogs against SARS-CoV-2: POM study and identification of the pharmacophore sites.
Anowar Hosen, Mohammed; Sultana Munia, Nasrin; Al-Ghorbani, Mohammed; Baashen, Mohammed; Almalki, Faisal A; Ben Hadda, Taibi; Ali, Ferdausi; Mahmud, Shafi; Abu Saleh, Md; Laaroussi, Hamid; Kawsar, Sarkar M A.
  • Anowar Hosen M; Laboratory of Carbohydrate and Nucleoside Chemistry, Department of Chemistry, Faculty of Science, University of Chittagong, Chittagong 4331, Bangladesh.
  • Sultana Munia N; Laboratory of Carbohydrate and Nucleoside Chemistry, Department of Chemistry, Faculty of Science, University of Chittagong, Chittagong 4331, Bangladesh.
  • Al-Ghorbani M; Department of Chemistry, Faculty of Science and Arts, Ulla, Taibah University, Medina, Saudi Arabia.
  • Baashen M; Department of Chemistry, Science and Humanities College, Shaqra University, Saudi Arabia.
  • Almalki FA; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm Al-Qura University, 21955 Makkah, Saudi Arabia.
  • Ben Hadda T; Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Umm Al-Qura University, 21955 Makkah, Saudi Arabia; Laboratory of Applied Chemistry & Environment, Faculty of Sciences, Mohammed Premier University, MB 524, 60000 Oujda, Morocco.
  • Ali F; Department of Microbiology, Faculty of Biological Science, University of Chittagong, V, Bangladesh.
  • Mahmud S; Microbiology Laboratory, Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi 6205, Bangladesh.
  • Abu Saleh M; Microbiology Laboratory, Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi 6205, Bangladesh.
  • Laaroussi H; Laboratory of Applied Chemistry & Environment, Faculty of Sciences, Mohammed Premier University, MB 524, 60000 Oujda, Morocco.
  • Kawsar SMA; Laboratory of Carbohydrate and Nucleoside Chemistry, Department of Chemistry, Faculty of Science, University of Chittagong, Chittagong 4331, Bangladesh. Electronic address: akawsarabe@yahoo.com.
Bioorg Chem ; 125: 105850, 2022 08.
Article in English | MEDLINE | ID: covidwho-1819433
ABSTRACT
Nucleoside precursors and nucleoside analogs occupy an important place in the treatment of viral respiratory pathologies, especially during the current COVID-19 pandemic. From this perspective, the present study has been designed to explore and evaluate the synthesis and spectral characterisation of 5́-O-(lauroyl) thymidine analogs 2-6 with different aliphatic and aromatic groups through comprehensive in vitro antimicrobial screening, cytotoxicity assessment, physicochemical aspects, molecular docking and molecular dynamics analysis, along with pharmacokinetic prediction. A unimolar one-step lauroylation of thymidine under controlled conditions furnished the 5́-O-(lauroyl) thymidine and indicated the selectivity at C-5́ position and the development of thymidine based potential antimicrobial analogs, which were further converted into four newer 3́-O-(acyl)-5́-O-(lauroyl) thymidine analogs in reasonably good yields. The chemical structures of the newly synthesised analogs were ascertained by analysing their physicochemical, elemental, and spectroscopic data. In vitro antimicrobial tests against five bacteria and two fungi, along with the prediction of activity spectra for substances (PASS), indicated promising antibacterial functionality for these thymidine analogs compared to antifungal activity. In support of this observation, molecular docking experiments have been performed against the main protease of SARS-CoV-2, and significant binding affinities and non-bonding interactions were observed against the main protease (6LU7, 6Y84 and 7BQY), considering hydroxychloroquine (HCQ) as standard. Moreover, the 100 ns molecular dynamics simulation process was performed to monitor the behaviour of the complex structure formed by the main protease under in silico physiological conditions to examine its stability over time, and this revealed a stable conformation and binding pattern in a stimulating environment of thymidine analogs. Cytotoxicity determination confirmed that compounds were found less toxic. Pharmacokinetic predictions were investigated to evaluate their absorption, distribution, metabolism and toxic properties, and the combination of pharmacokinetic and drug-likeness predictions has shown promising results in silico. The POM analysis shows the presence of an antiviral (O1δ-, O2δ-) pharmacophore site. Overall, the current study should be of great help in the development of thymidine-based, novel, multiple drug-resistant antimicrobial and COVID-19 drugs.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Experimental Studies / Observational study / Prognostic study / Randomized controlled trials Limits: Humans Language: English Journal: Bioorg Chem Year: 2022 Document Type: Article Affiliation country: J.bioorg.2022.105850

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Full text: Available Collection: International databases Database: MEDLINE Main subject: SARS-CoV-2 / COVID-19 Drug Treatment Type of study: Experimental Studies / Observational study / Prognostic study / Randomized controlled trials Limits: Humans Language: English Journal: Bioorg Chem Year: 2022 Document Type: Article Affiliation country: J.bioorg.2022.105850