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Anti-COVID-19 activity of some benzofused 1,2,3-triazolesulfonamide hybrids using in silico and in vitro analyses.

ABSTRACT: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pandemic fatal infection with no known treatment. The severity of the disease and the fast viral mutations forced the scientific community to search for potential solution. Here in the present manuscript, some benzofused1,2,3triazolesulfonamide hybrids were synthesized and evaluated for their anti- SARS-CoV-2 activity using in silico prediction then the most potent compounds were assessed using in-Vitro analysis. The in-Silico study was assessed against RNA dependent RNA polymerase, Spike protein S1, Main protease (3CLpro) and 2'-O-methyltransferase (nsp16). It was found that 4b and 4c showed high binding scores against RNA dependent RNA polymerase reached -8.40 and -8.75 kcal/mol, respectively compared to the approved antiviral (remdesivir -6.77 kcal/mol). Upon testing the binding score with SARS-CoV-2 Spike protein it was revealed that 4c exhibited the highest score (-7.22 kcal/mol) compared to the reference antibacterial drug Ceftazidime (-6.36 kcal/mol). Surprisingly, the two compounds 4b and 4c showed the highest binding scores against SARS-CoV-2 3CLpro (-8.75, -8.48 kcal/mol, respectively) and nsp16 (- 8.84 and - 8.89 kcal/mol, respectively) displaying many types of interaction with all the enzymes binding sites. The derivatives 4b and 4c were examined in vitro for their potential anti-SARS-CoV-2 and it was revealed that 4c was the most promising compound with IC50 reached 758.8108 mM and complete (100%) inhibition of the binding of SARS-CoV-2 virus to human ACE2 can be accomplished by using 0.01 mg.

SUBMITTER: Alzahrani AY

PROVIDER: S-EPMC8434689 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:A series of new coumarin-N-heterocyclic hybrids, coumarin-quinolines 7a-e, coumarin-acridines 10b,c and coumarin-neocryptolepines 13b,c were synthesized and evaluated for their anticancer and antimicrobial activities. The structures of all synthesized hybrids were confirmed by FT-IR, 1H-NMR, 13C-NMR, and MS spectrometry. The anti-proliferative activity of hybrids 7a-e, 10c and 13c were bio-evaluated using MTT-assay against colon (CaCo-2), lung (A549), breast (MDA-MB-231), and hepatocellular carcinoma (HepG-2) human cancer cell lines using doxorubicin as a reference drug. The results demonstrated that, all hybrids displayed moderate to good anti-proliferative activity against the cell lines. The most active hybrids were 7a-d and 10c against CaCo-2 cancer cell line with IC50: 57.1, 52.78, 57.29, 51.95 and 56.74 µM, and selectivity index 1.38, 1.76, 2.6, 1.96 and 0.77; respectively. While, 7a,d were potent against A549 cancer cell line with IC50: 51.72, 54.8 µM and selectivity index 1.5, 0.67; respectively. Moreover, 7c showed the most potency against MDA-MB-231 cancer cell line with IC50: 50.96 µM and selectivity index 2.20. Interestingly, docking results revealed that binding energy of the current compounds showed marked affinity values ranging from -6.54 to -5.56 kcal with interactions with the reported key amino acid SER 79. Furthermore, the antimicrobial activity of the synthesized hybrids 7a-e, 10b,c, 13b and 13c were evaluated against Gram-positive and Gram-negative bacterial and fungal strains. The hybrids 10b, 13b, 10c, and 13c exhibited broad-spectrum antibacterial activity against E.coli, S. mutans, and S. aureus with MIC from 3.2 to 66 µM, this hybrids also displayed antifungal activity against C. albicans with MIC values ranging from 0.0011 to 29.5 µM. In-silico investigation of the pharmacokinetic properties indicated that tested hybrids had high GI absorption, low Blood Brain Barrier (BBB) permeability in addition to cell membrane penetrability.

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Anti-COVID-19 activity of some benzofused 1,2,3-triazolesulfonamide hybrids using in silico and in vitro analyses.

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