Most estrogen receptor α (ERα) ligands target the ligand binding domain (LBD). Agonist 17β-estradiol (E 2 ) and tamoxifen (TM, known SERM), bind to the same site within the LBD. However, structures of ligand-bound complexes show that E 2 and TM induce different conformations of helix 12 (H12). During the molecular modelling studies of some naturally occurring flavonoids such as quercetin, luteolin, myricetin, kaempferol, naringin, hesperidin, galangin, baicalein and epicatechin with human ERα (3ERT and 1GWR), we observed that most of the ligands bound to the active site pocket of both 3ERT and 1GWR. The docking scores, interaction analyses, and conformation of H12 provided the data to support for the estrogenic or antiestrogenic potential of these flavonoids to a limited degree. Explicit molecular dynamics for 50 ns was performed to identify the stability and compatibility pattern of protein-ligand complex and RMSD were obtained. Baicalein, epicatechin, and kaempferol with 1GWR complex showed similar RMSD trend with minor deviations in the protein backbone RMSD against 1GWR-E 2 complex that provided clear indications that ligands were stable throughout the explicit molecular simulations in the protein and outcome of naringin-3ERT complex had an upward trend but stable throughout the simulations and all molecular dynamics showed stability with less than overall 1 Å deviation throughout the simulations. To examine their estrogenic or antiestrogenic potential, we studied the effect of the flavonoids on viability, progesterone receptor expression and 3xERE/3XERRE-driven reporter gene expression in ERα positive and estrogen responsive MCF-7 breast cancer cells. Epicatechin, myricetin, and kaempferol showed estrogenic potential at 5 µM concentration.

Novel drug regimens against tuberculosis (TB) are urgently needed and may be developed by targeting essential enzymes of Mtb that sustain the pathogenicity of tuberculosis. Dihydrorugosaflavonoid interacted with the active pocket of MabA and PanK.

Ligand interaction of 6f with 1M17.

Antiviral therapy is crucial for the circumvention of viral epidemics. The unavailability of a specific antiviral drug against the chikungunya virus (CHIKV) disease has created an alarming situation to identify or develop potent chemical molecules for remedial management of CHIKV. In the present investigation, in silico studies of dihydrorugosaflavonoid derivatives (5a–f) with non-structural protein-3 (nsP3) were carried out. nsP3 replication protein has recently been considered as a possible antiviral target in which crucial inhibitors fit into the adenosine-binding pocket of the macrodomain. The 4′-halogenated dihydrorugosaflavonoids displayed intrinsic binding with the nsp3 macrodomain (PDB ID: 3GPO) of CHIKV. Compounds 5c and 5d showed docking scores of −7.54 and −6.86 kcal mol–1, respectively. Various in vitro assays were performed to confirm their (5a–f) antiviral potential against CHIKV. The non-cytotoxic dose was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and was found to be <100 μM. The compounds 5c and 5d showed their inhibitory potential for CHIKV, which was determined through cytopathic effect assay and plaque reduction assay, which show inhibition up to 95 and 92% for 70 μM concentration of the compounds, respectively. The quantitative real-time polymerase chain reaction assay result confirmed the ability of 5c and 5d to reduce the viral RNA level at 70 μM concentration of compounds to nearly 95 and 93% concentration, respectively, in cells with CHIKV infection. Further, the CHIKV-inhibitory capacity of these compounds was corroborated by execution of immunofluorescence assay. The executed work will be meaningful for the future research of studied dihydrorugosaflavonoids against prime antiviral entrants, leading to remedial management to preclude CHIKV infection.

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The first synthetic route developed for Podocarflavone A reported from Podocarpus macrophyllus and its analogs in 7 steps. Computational analysis for binding with the pantothenate kinase (3AVO) of Mycobacterium tuberculosis showed their ds in the range of -8.9 to -9.3 Kcal/mol. MD simulations delineated the stability of the protein-ligand complexes in the TIP3P model. MMGBSA and MMPBSA values of 8d were -42.46 Kcal/mol and -14.58 Kcal/mol, respectively. Further in-vitro screening of 8a, 8d, and 8e against M. tuberculosis H37Ra using XRMA protocol exhibited antimycobacterial activity with IC50 values 21.82 µg/mL, 15.55, and 16.56 µg/mL, respectively. Compounds 8a, 8d, and 8e showed antibacterial activity with IC50 values 41.56 µg/mL, 24.72 µg/mL, and 72.45 µg/mL respectively against the Staphylococcus aureus. 8a and 8d showed inhibition with IC50 values 39.6 µg/mL and 27.64 µg/mL, respectively, against Bacillus subtilis. The present study could help in the further development of lead molecules against tuberculosis.

Looking at the severity of SARS-CoV-2 even after the approval of several vaccines like Covishield and Covaxin, there is a concern to find a fruitful remedy for treating infected people in the whole world to stop the spreading of this virus. In this piece of work, we systematically carried out the computational study of potent natural flavonoids Podocarflavone A and Rugosaflavonoid A and their analogs with many targets of COVID-19 such as main Protease (6LU7), S-protein and human ACE2 receptor Complex (6VW1), and RdRp (6M71), which are essential for the survival of nCov-19. MD simulations for 50ns were carried out in TIP3P to check their stability. Thermodynamic stability of the receptor-ligand complexes was evaluated with MMGBSA, and MMPBSA study. The Podocarflavone A and dihydrorugosaflavonoid analogs showed effective binding energy (DS -8.8 to -8.0 Kcal/mol) with S-protein and human ACE2 receptor Complex (6VW1), Protease (6LU7), and RdRp (6M71) of COVID-19. The comparative analysis with several standard antivirals such as remdesivir, oseltamivir, lopinavir, sofosbuvir, tenofovir, galidesivir, and favipiravir displayed that these natural analogs can be better antiviral for the COVID-19. This study demonstrated that halogenated Podocarflavone 2b (MMGBSA -40.93 Kcal/mol, MMPBSA -14.16 Kcal/mol) has comparable results with lopinavir (MMGBSA -43.15 Kcal/mol, MMPBSA -11.89 Kcal/mol). These compounds could be selected for wet-lab screening to develop as lead molecules in the initial infective stage with spike protein and replicative stage with RdRp of the n-Cov-19 virus.

The first synthetic route of naturally occurring (±)-5,7-dihydroxy-8-methyl-3-(2',4'dihydroxybenzyl)chroman-4-one (1) from Gan Luo Xin pill was successfully accomplished.The synthetic route has been developed retro-synthetically in 9 simple steps with a high yield of ~80 %. The synthetic protocol was developed using readily available starting material phloroglucinol. The key intermediate 2,4,6-trihydroxy-3-methyl acetophenone (4) was synthesized via Vilsmeier-Haack reaction, followed by reduction using sodium cyanoborohydride and acylation reaction. LC-MS, IR, 1 H NMR, 13 C NMR of 1 have been analyzed to confirm the structure of (±)-5,7-dihydroxy-8-methyl-3-(2',4'dihydroxybenzyl)chroman-4-one (1) and found in agreement with the natural molecule. The target compound showed 97% and 87% antioxidant activity in DPPH and ABTS assay at 1mg/ml concentration, respectively. The compound (1) also showed ferric ion reducing activity with the absorbance of 0.18 at 700nm. The present study could be useful in developing synthetic routes of other potential naturally occurring homoisoflavonoid. ST1:Table 1: Comparative analysis of data of (±)-5,7-dihydroxy-8-methyl-3-(2',4'dihydroxybenzyl)chroman-4-one isolated from Gan Luo Xin and synthesized in the laboratory. (±)-5,7-dihydroxy-8methyl-3-(2',4'dihydroxybenzyl) chroman-4-one.