Glycyrrhizin as a promising kryptonite against SARS-CoV-2: Clinical, experimental, and theoretical evidences.

COVID-19 is the most devastating disease in recent times affecting most people globally. The higher rate of transmissibility and mutations of SARS-CoV-2 along with the lack of potential therapeutics has made it a global crisis. Potential molecules from natural sources could be a fruitful remedy to combat COVID-19. This systematic review highlights the detailed therapeutic implication of naturally occurring glycyrrhizin and its related derivatives against COVID-19. Glycyrrhizin has already been established for blocking different biomolecular targets related to the SARS-CoV-2 replication cycle. In this article, several experimental and theoretical evidences of glycyrrhizin and related derivatives have been discussed in detail to evaluate their potential as a promising therapeutic strategy against COVID-19. Moreover, the implication of glycyrrhizin in traditional Chinese medicines for alleviating the symptoms of COVID-19 has been reviewed. The potential role of glycyrrhizin and related compounds in affecting various stages of the SARS-CoV-2 life cycle has also been discussed in detail. Derivatization of glycyrrhizin for designing potential lead compounds along with combination therapy with other anti-SARS-CoV-2 agents followed by extensive evaluation may assist in the formulation of novel anti-coronaviral therapy for better treatment to combat COVID-19.

Protease targeted COVID-19 drug discovery and its challenges: Insight into viral main protease (Mpro) and papain-like protease (PLpro) inhibitors.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) brutally perils physical and mental health worldwide. Unavailability of effective anti-viral drug rendering global threat of COVID-19 caused by SARS-CoV-2. In this scenario, viral protease enzymes are crucial targets for drug discovery. This extensive study meticulously focused on two viral proteases such as main protease (Mpro) and papain-like protease (PLpro), those are essential for viral replication. This review provides a detail overview of the targets (Mpro and PLpro) from a structural and medicinal chemistry point of view, together with recently reported protease inhibitors. An insight into the challenges in the development of effective as well as drug like protease inhibitors is discussed. Peptidomimetic and/or covalent coronavirus protease inhibitors possessed potent and selective active site inhibition but compromised in pharmacokinetic parameters to be a drug/drug like molecule. Lead optimization of non-peptidomimetic and/or low molecular weight compounds may be a better option for oral delivery. A masterly combination of adequate pharmacokinetic properties with coronavirus protease activity as well as selectivity will provide potential drug candidates in future. This study is a part of our endeavors which surely dictates medicinal chemistry efforts to discover effective anti-viral agent for this devastating disease.

Robust design of some selective matrix metalloproteinase-2 inhibitors over matrix metalloproteinase-9 through in silico/fragment-based lead identification and de novo lead modification: Syntheses and biological assays.

Broad range of selectivity possesses serious limitation for the development of matrix metalloproteinase-2 (MMP-2) inhibitors for clinical purposes. To develop potent and selective MMP-2 inhibitors, initially multiple molecular modeling techniques were adopted for robust design. Predictive and validated regression models (2D and 3D QSAR and ligand-based pharmacophore mapping studies) were utilized for estimating the potency whereas classification models (Bayesian and recursive partitioning analyses) were used for determining the selectivity of MMP-2 inhibitors over MMP-9. Bayesian model fingerprints were used to design selective lead molecule which was modified using structure-based de novo technique. A series of designed molecules were prepared and screened initially for inhibitions of MMP-2 and MMP-9, respectively, as these are designed followed by other MMPs to observe the broader selectivity. The best active MMP-2 inhibitor had IC50 value of 24nM whereas the best selective inhibitor (IC50=51nM) showed at least 4 times selectivity to MMP-2 against all tested MMPs. Active derivatives were non-cytotoxic against human lung carcinoma cell line-A549. At non-cytotoxic concentrations, these inhibitors reduced intracellular MMP-2 expression up to 78% and also exhibited satisfactory anti-migration and anti-invasive properties against A549 cells. Some of these active compounds may be used as adjuvant therapeutic agents in lung cancer after detailed study.

A new bisbenzylisoquinoline alkaloid isolated from Thalictrum foliolosum, as a potent inhibitor of DNA topoisomerase IB of Leishmania donovani.

Chemical investigation of the stem of Thalictrum foliolosum resulted in the isolation of two new bisbenzylisoquinoline alkaloids (1 and 2) along with known protoberberine group of isoquinoline alkaloids thalifendine (3) and berberine (4). The structures of the new compounds were established by detailed 2D NMR spectral analysis with their configurations determined from their optical rotation values and confirmed using circular dichroism. Inhibitory activities of these four compounds against DNA topoisomerase IB of Leishmania donovani were evaluated. Compound 2 exhibited almost complete inhibition of the enzyme activity at 50 µM concentration and it was found to be effective in killing both wild type as well as SAG resistant promastigotes of the parasite.

Anthocephaline, a new indole alkaloid and cadambine, a potent inhibitor of DNA topoisomerase IB of Leishmania donovani (LdTOP1LS), isolated from Anthocephalus cadamba.

Chemical investigation of the stem bark of Anthocephalus cadamba has resulted in the isolation of anthocephaline (1), a new indole alkaloid, along with strictosamide (2), vincosamide (3) and cadambine (4). The structures of the isolated alkaloids (1-4) were established by detailed 2D NMR spectral analysis. Cadambine (4) exhibited potent DNA topoisomerase IB inhibitory activity.

Spermicidal and contraceptive potential of desgalactotigonin: a prospective alternative of nonoxynol-9.

Crude decoction of Chenopodium album seed showed spermicidal effect at MIC 2 mg/ml in earlier studies. Systematic isolation, characterization and evaluation revealed that the major metabolite Desgalactotigonin (DGT) is the most effective principle in both in vitro and in vivo studies. The in vitro studies comprises (a) rat and human sperm motility and immobilizing activity by Sander-Cramer assay; (b) sperm membrane integrity was observed by HOS test and electron microscopy; (c) microbial potential was examined in Lactobacillus broth culture, and (d) the hemolytic index was determined by using rat RBCs. The in vivo contraceptive efficacy was evaluated by intra uterine application of DGT in rat. Lipid peroxidation and induction of apoptosis by DGT on human spermatozoa were also studied. The minimum effective concentration (MEC) of DGT that induced instantaneous immobilization in vitro was 24.18 µM for rat and 58.03 µM for human spermatozoa. Microbial study indicated DGT to be friendly to Lactobacillus acidophilus. Implantation was prevented in DGT treated uterine horn while no hindrance occurred in the untreated contra lateral side. At the level of EC50, DGT induced apoptosis in human spermatozoa as determined by increased labeling with Annexin-V and decreased polarization of sperm mitochondria. Desgalactotigonin emerged 80 and 2×10(4) times more potent than the decoction and Nonoxynol-9 respectively. It possesses mechanism based detrimental action on both human and rat spermatozoa and spares lactobacilli and HeLa cells at MEC which proves its potential as a superior ingredient for the formulation of a contraceptive safer/compatible to vaginal microflora.

A new ellagic acid glycoside and DNA topoisomerase IB inhibitory activity of saponins from Putranjiva roxburghii.

Chemical investigation of the stem bark and leaves of Putranjiva roxburghii has resulted in the isolation of a new ellagic acid glycoside (5) along with four saponins (1-4). The structures of the isolated compounds were established by detailed spectral analysis. Incidentally putranoside-A methyl ester (4) has been isolated for the first time from this species and the saponins (1-4) exhibited potent DNA topoisomerase IB inhibitory activity.

Exploration of structural and physicochemical requirements and search of virtual hits for aminopeptidase N inhibitors.

Aminopeptidase N (APN) inhibitors have been reported to be effective in treating of life threatening diseases including cancer. Validated ligand- and structure-based pharmacophore mapping approaches were combined with Bayesian modeling and recursive partitioning to identify structural and physicochemical requirements for highly active APN inhibitors. Based on the assumption that ligand- and structure-based pharmacophore models are complementary, the efficacy of 'multiple pharmacophore screening' for filtering true positive virtual hits was investigated. These multiple pharmacophore screening methods were utilized to search novel virtual hits for APN inhibition. The number of hits was refined and reduced by recursive partitioning, drug-likeliness, pharmacokinetic property prediction, and comparative molecular-docking studies. Four compounds were proposed as the potential virtual hits for APN enzyme inhibition.

Antibacterial activity of Abies webbiana.

The methanol extract of the dried leaves of Abies webbiana was evaluated for antimicrobial activity. The methanol extract showed a broad spectrum of antibacterial activity.

Synergistic effect of methanol extract of Abies webbiana leaves on sleeping time induced by standard sedatives in mice and anti-inflammatory activity of extracts in rats.

During the determination of LD50 values of extracts of Abies webbiana, it was observed that the methanol extract (MEAW) produces sedation of animals. This led to investigation of the effect of MEAW on sleeping time in mice. When various doses of the methanol extract (100, 150, and 200 mg/kg body weight) were administered alone, no hypnotic activity was observed. However, these exhibited significant synergistic effects (P < 0.001) at those dose levels in mice when administered prior to the administration of standard sedatives (pentobarbitone sodium: 50 mg/kg and diazepam: 6 mg/kg, respectively). In addition anti-inflammatory effects of methanol, chloroform, and petroleum ether extracts of Abies webbiana leaves in rats were performed to assess scientific validity of the medicinal claim of Indian folk medicine. The effects of leaf extracts (methanol, chloroform, and petroleum ether) against inflammation were studied by carrageenan-induced paw edema model in rats. The methanol extract (400 mg/kg p.o.) of leaves of Abies webbiana showed the best significant anti-inflammatory activity as compared to that of diclofenac sodium (150 mg/kg p.o.). The LD50 values of methanol, chloroform, and petroleum ether extracts were found to be 986, 1387, and > 3200 mg/kg, respectively. Thus, the therapeutic index of methanol extract may be favorable to open a new vista on combination therapy of hypnotics and may also against inflammation.