The persistent evolution of
drug-resistant
influenza strains represents a global concern. The innovation of new treatment approaches through
drug screening strategies and investigating the
antiviral potential of bioactive natural-based chemicals may address the issue. Herein, we screened the anti-
influenza efficacy of some biologically active
indole and β-
carboline (βC)
indole alkaloids against two different influenza A viruses (IAV) with varied host range ranges; seasonal
influenza A/Egypt/NRC098/2019(H1N1) and
avian influenza A/chicken/Egypt/N12640A/2016(H5N1). All compounds were first assessed for their half-maximal cytotoxic concentration (CC50) in MDCK cells and half-maximal inhibitory concentrations (IC50) against
influenza A/H5N1. Intriguingly,
Strychnine sulfate,
Harmalol,
Harmane, and
Harmaline showed robust anti-H5N1 activities with IC50 values of 11.85, 0.02, 0.023, and 3.42 µg/ml, respectively, as compared to
zanamivir and
amantadine as control drugs (IC50 = 0.079 µg/ml and 17.59 µg/ml, respectively). The efficacy of the predefined
phytochemicals was further confirmed against
influenza A/H1N1 and they displayed potent anti-H1N1 activities compared to reference drugs. Based on SI values, the highly promising compounds were then evaluated for
antiviral efficacy through plaque reduction assay and consistently they revealed high viral inhibition percentages at non-toxic concentrations. By studying the modes of
antiviral action,
Harmane and
Harmalol could suppress
viral infection via interfering mainly with the viral replication of the
influenza A/H5N1 virus, whilst
Harmaline exhibited a viricidal effect against the
influenza A/H5N1 virus. Whereas,
Strychnine sulfate elucidated its anti-
influenza potency by interfering with viral adsorption into MDCK cells. Consistently, chemoinformatic studies showed that all studied
phytochemicals illustrated HB formations with essential
peptide cleft through the NH of
indole moiety. Among active
alkaloids,
harmalol displayed the best lipophilicity metrics including
ligand efficiency (LE) and
ligand lipophilic efficiency (LLE) for both viruses. Compounds geometry and their ability to participate in HB formation are very crucial.