Design, synthesis, graph theoretical analysis and molecular modelling studies of novel substituted quinoline analogues as promising anti-breast cancer agents.

The most promising class of heterocyclic compounds in medicinal chemistry are those with the quinolin-2-one nucleus. It is a versatile heterocyclic molecule that has been put together with numerous pharmaceutical substances and is crucial in the creation of anticancer medications. In this view, the present research work deals with design, synthesis, and characterization of various analogous of quinolin-2-one nucleus and evaluation of their anticancer activity against MCF-7 cells (adenoma breast cancer cell line). Fourteen new compounds have been synthesised using suitable synthetic route and are characterized by FTIR, 1H NMR, 13C NMR and Mass spectral data. Molecular docking studies of the title compounds were carried out using PyRx 0.8 tool in AutoDock Vina program. All the synthesised compounds were exhibited well conserved hydrogen bonding with one or more amino acid residues in the active pocket of EGFR tyrosine kinase (PDB ID: 1m17). The docking score of the derivatives ranged from - 6.7 to - 9.5 kcal mol-1, standard drug Imatinib with - 9.6 kcal mol-1 and standard active ligand 4-anilinoquinazoline with - 7.7 kcal mol-1. The designed compound IV-A1 showed least binding energy (- 9.5 kcal mol-1) against EGFR tyrosine kinase receptor. Further, top scored compound, IV-A1 found to be most significant against MCF-7 cells with IC50 value of 0.0870 µM mL-1, TGI of 0.0958 µM mL-1, GI50 of 0.00499 µM mL-1, LC50 of 1.670 µM mL-1.

Design, Synthesis, and Antimycobacterial Evaluation of Novel Tetrahydroisoquinoline Hydrazide Analogs.

A series of novel 2-substituted-5,7-dichloro-1,2,3,4-tetrahydroisoquinoline-6-carbohydrazide were designed, synthesized and structures were confirmed by analytical methods, viz., 1 H-NMR, 13 C-NMR and Mass spectrometry. Synthesized derivatives were evaluated for their anti-mycobacterial activity against Mycobacterium tuberculosis (Mtb) H37Ra. Among all the evaluated compounds, 10A25 containing biphenyl moiety exhibited significant inhibition with IC50 4.7 µM. 10A19, with an electron-withdrawing Iodo group in the ortho position of the phenyl exhibited significant anti-tubercular activity with IC50 8.8 µM. IC50 values of the remaining compounds ranged from 9.2 to 73.6 µM. Molecular docking study of the significantly active compound 10A25 was performed to determine the putative binding position of the test ligand at the active site of the selected target proteins Mycobacterium tuberculosis enoyl reductase (InhA) PDB - 4TZK and peptide deformylase PDB - 3E3U. A suitable single crystal for one of the active compounds, 10A12, was generated and analysed to further confirm the structure of the compounds.

Spotlight on 4-substituted quinolines as potential anti-infective agents: Journey beyond chloroquine.

Continued emerging resistance of pathogens against the clinically approved candidates and their associated limitations continuously demand newer agents having better potency with a more suited safety profile. Quinoline nuclei containing scaffolds of natural and synthetic origin have been documented for diverse types of pharmacological activities, and a number of drugs are clinically approved. In the present review, we unprecedentedly covered the biological potential of 4-substituted quinoline and elaborated a rationale for its special privilege to afford the significant number of approved clinical drugs, particularly against infectious pathogens. Compounds with 4-substituted quinoline are well documented for antimalarial activity, but in the last two decades, they have been extensively explored for activity against cancer, tuberculosis, and several other pathogens including viruses, bacteria, fungi, and other infectious pathogens. In the present study, the anti-infective spectrum of this scaffold is discussed against viruses, mycobacteria, malarial parasites, and fungal and bacterial strains, along with recent updates in this area, with special emphasis on the structure-activity relationship.

Design, Synthesis, and Biological Evaluation of Novel Quinazolin-4(3H)-One-Based Histone Deacetylase 6 (HDAC6) Inhibitors for Anticancer Activity.

A series of novel quinazoline-4-(3H)-one derivatives were designed and synthesized as histone deacetylase 6 (HDAC6) inhibitors based on novel quinazoline-4-(3H)-one as the cap group and benzhydroxamic acid as the linker and metal-binding group. A total of 19 novel quinazoline-4-(3H)-one analogues (5a-5s) were obtained. The structures of the target compounds were characterized using 1H-NMR, 13C-NMR, LC-MS, and elemental analyses. Characterized compounds were screened for inhibition against HDAC8 class I, HDAC4 class IIa, and HDAC6 class IIb. Among the compounds tested, 5b proved to be the most potent and selective inhibitor of HDAC6 with an IC50 value 150 nM. Some of these compounds showed potent antiproliferative activity in several tumor cell lines (HCT116, MCF7, and B16). Amongst all the compounds tested for their anticancer effect against cancer cell lines, 5c emerged to be most active against the MCF-7 line with an IC50 of 13.7 µM; it exhibited cell-cycle arrest in the G2 phase, as well as promoted apoptosis. Additionally, we noted a significant reduction in the colony-forming capability of cancer cells in the presence of 5c. At the intracellular level, selective inhibition of HDAC6 was enumerated by monitoring the acetylation of α-tubulin with a limited effect on acetyl-H3. Importantly, the obtained results suggested a potent effect of 5c at sub-micromolar concentrations as compared to the other molecules as HDAC6 inhibitors in vitro.

Novel thiophene Chalcones-Coumarin as acetylcholinesterase inhibitors: Design, synthesis, biological evaluation, molecular docking, ADMET prediction and molecular dynamics simulation.

A series of around eight novel chalcone based coumarin derivatives (23a-h) was designed, subjected to in-silico ADMET prediction, synthesized, characterized by IR, NMR, Mass analytical techniques and evaluated as acetylcholinesterase (AChE) inhibitor for the treatment of Alzheimer's disease (AD). The results of predicted ADMET study demonstrated the drug-likeness properties of the titled compounds with developmental challenges in lipophilicity and solubility parameters. The in vitro assessment of the synthesized compounds revealed that all of them showed significant activity (IC50 ranging from 0.42 to 1.296 µM) towards AChE compared to the standard drug, galantamine (IC50 = 1.142 ±â€¯0.027 µM). Among these, compound 23e displayed the most potent inhibitory activity with IC50 value of 0.42 ±â€¯0.019 µM. Cytotoxicity of all compounds was tested on normal human hepatic (THLE-2) cell lines at three different concentrations using the MTT assay, in which none of the compound showed significant toxicity at the highest concentration of 1000 µg/ml compared to the control group. Based on the docking study against AChE, the most active derivative 23e was orientated towards the active site and occupied both catalytic anionic site (CAS) and peripheral anionic site (PAS) of the target enzyme. In-silico studies revealed tested showed better inhibition activity of AChE compared to Butyrylcholinesterase (BuChE). Molecular dynamics simulation explored the stability and dynamic behavior of 23e- AChE complex.

Design, Synthesis and Biological Evaluation of Novel Spiro-[Chroman-2,4'-Piperidin]-4-One Analogs as Anti-Tubercular Agents.

A series of novel spiro-[chromane-2,4'-piperidin]-4(3H)-one derivatives were designed, synthesized and structures were confirmed by analytical methods, viz., 1 H-NMR, 13 C-NMR and mass spectrometry. The synthetic derivatives were evaluated for their anti-tuberculosis (anti-TB) activity against Mycobacterium tuberculosis (Mtb) strain H37Ra. Among all the evaluated Compounds, PS08 exhibited significant inhibition with MIC value of 3.72 µM while MIC values of the remaining Compounds ranged from 7.68 to 230.42 µM in comparison to the standard drug INH (MIC 0.09 µM). The two most active Compounds however showed acute cytotoxicity towards the human MRC-5 lung fibroblast cell lines. The in silico ADMET profiles of the titled Compounds were predicted and found within the prescribed limits of the Lipinski and Jorgenson rules. Molecular docking study of the notably active Compound (PS08) was also carried out after performing validation in order to understand the putative binding position of the test ligand at the active site of selected target protein Mtb tyrosine phosphatase (PtpB).

Systematic Down-Selection of Repurposed Drug Candidates for COVID-19.

SARS-CoV-2 is the cause of the COVID-19 pandemic which has claimed more than 6.5 million lives worldwide, devastating the economy and overwhelming healthcare systems globally. The development of new drug molecules and vaccines has played a critical role in managing the pandemic; however, new variants of concern still pose a significant threat as the current vaccines cannot prevent all infections. This situation calls for the collaboration of biomedical scientists and healthcare workers across the world. Repurposing approved drugs is an effective way of fast-tracking new treatments for recently emerged diseases. To this end, we have assembled and curated a database consisting of 7817 compounds from the Compounds Australia Open Drug collection. We developed a set of eight filters based on indicators of efficacy and safety that were applied sequentially to down-select drugs that showed promise for drug repurposing efforts against SARS-CoV-2. Considerable effort was made to evaluate approximately 14,000 assay data points for SARS-CoV-2 FDA/TGA-approved drugs and provide an average activity score for 3539 compounds. The filtering process identified 12 FDA-approved molecules with established safety profiles that have plausible mechanisms for treating COVID-19 disease. The methodology developed in our study provides a template for prioritising drug candidates that can be repurposed for the safe, efficacious, and cost-effective treatment of COVID-19, long COVID, or any other future disease. We present our database in an easy-to-use interactive interface (CoviRx that was also developed to enable the scientific community to access to the data of over 7000 potential drugs and to implement alternative prioritisation and down-selection strategies.

Identification of Papain-Like Protease inhibitors of SARS CoV-2 through HTVS, Molecular docking, MMGBSA and Molecular dynamics approach.

Coronaviruses (CoVs) are a large group of enveloped positive sense single-stranded RNA viruses that can cause disease to humans. These are zoonotic having potential to cause large-scale outbreaks of infections widely causing morbidity and mortality. Papain-Like Protease (PLpro) is a cysteine protease, essential for viral replication and proliferation, as a highly conserved enzyme it cleaves peptide linkage between Nsp1, Nsp2, Nsp3, and Nsp4. As a valid therapeutic target, it stops viral reproduction and boosts host immune response thereby halting further spread of infection. In the purpose of identifying inhibitors targeting Papain-Like Proteases (PLpro) we initiated a high throughput virtual screening (HTVS) protocol using a SuperNatural Database. The XP docking results revealed that two compounds SN00334175 and SN00162745 exhibited docking scores of -10.58 kcal/mol and -9.93 kcal/mol respectively. The Further PRIME MMGB-SA studies revealed Van der Waal energy and hydrophobic energy terms as major contributors for total binding free energy. The 100 ns molecular dynamics simulation of SN00334175/7JN2 and SN00162745/7JN2 revealed that these complexes were stabilized with ligand binding forming interactions with Gly266, Asn267, Tyr268, Tyr273, Thr301 and Asp302, Lys157, Leu162, Asp164, Arg166, Glu167, Pro248 and Tyr264.

Design, synthesis and biological evaluation of 7-(5-((substituted - amino)-methyl)-thiophen-2-yl)-spiro-[chroman-2,4'-piperidin]-4-one hydrochloride analogues as anticancer agents.

A series of thirty-one novel 7-(5-((amino)-methyl)-thiophen-2-yl)-spiro-[chroman-2,4'-piperidin]-4-one hydrochloride analogues (Cst 1 - 31) have been designed, synthesized and characterized by 1H NMR, 13C NMR and MS spectral analysis. Here, we evaluated the anticancer potential and biological results of low-molecular-weight bridgehead oxygen and nitrogen-containing spirochromanones on proliferation and apoptosis of the human breast cancer cell line (MCF-7) and Murine melanoma (B16F10). The anticancer activity ranged from 2.9 to 35.0 µM. The most potent compounds Cst-22, Cst-24 and Cst-31 were found to be less toxic against human embryonic kidney (HEK-293) cell lines. Cst-24 and Cst-31 were found to be causing significant cytotoxicity through apoptotic cell death and also G2 phase arrest of cell cycle in B16F10 cells. In-silico ADME prediction stidies of the titled compounds were found within the rules outlined, and these compounds may not face any pharmacokinetic associated issues in the mere future upon developmental stage. These conjugates may serve as a lead for the discovery of potential anticancer drug candidate with better therapeutic profile.

Novel phenanthridine amide analogs as potential anti-leishmanial agents: In vitro and in silico insights.

In the current work, sixteen novel amide derivatives of phenanthridine were designed and synthesized using 9-fluorenone, 4-Methoxy benzyl amine, and alkyl/aryl acids. The characterization of the title compounds was performed using LCMS, elemental analysis, 1HNMR, 13CNMR and single crystal XRD pattern was also developed for compounds A8. All the final analogs were screened in vitro for anti-leishmanial activity against promastigote form of L. infantum strain. Among the tested analogs, four compounds (A-06, A-11, A-12, and A-15) exhibited significant anti-leishmanial activity with EC50 value ranges from 8.9 to 21.96 µM against amastigote forms of tested L. infantum strain with SI ranges of 1.0 to 4.3. From the activity results it was found that A-11 was the most active compound in both promastigote and amastigotes forms with EC50 values 8.53 and 8.90 µM respectively. In-silico ADME prediction studies depicted that the titled compounds obeyed Lipinski's rule of five as that of the approved marketed drugs. The predicted in-silico toxicity profile also confirmed that the tested compounds were non-toxic. Finally, molecular docking and molecular dynamics study was also performed for significantly active compound (A-11) in order to study it's putative binding pattern at the active site of the selected leishmanial trypanothione reductase target as well as to understand the stability pattern of target-ligand complex for 100 ns. Single crystal XRD of compound A-08 revealed that the compound crystallizes in monoclinic C2/c space group and showed interesting packing arrangements.

Discovery of 1,2,3-triazole based quinoxaline-1,4-di-N-oxide derivatives as potential anti-tubercular agents.

A series of thirty one novel 2-(((1-(substituted phenyl)-1H-1,2,3-triazol-4-yl)methoxy)carbonyl)-3-methylquinoxaline-1,4-dioxide (7a-l), 3-(((1-(substituted phenyl)-1H-1,2,3-triazol-4-yl)methoxy)carbonyl)-6-chloro-2-methylquinoxaline-1,4-dioxide (8a-l) and 2-(((1-(substituted phenyl)-1H-1,2,3-triazol-4-yl)methoxy)carbonyl)-6,7-dichloro-3-methylquinoxaline-1,4-dioxide (9a-g) analogues were synthesized, characterized using various analytical techniques and single crystal was developed for the compounds 8 g and 9f. Synthesized compounds were evaluated for in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain and two clinical isolates Spec. 210 and Spec. 192. The titled compounds exhibited minimum inhibitory concentration (MIC) ranging from 30.35 to 252.00 µM. Among the tested compounds, 8e, 8 l, 9c and 9d exhibited moderate activity (MIC = 47.6 - 52.0 µM) and 8a exhibited significant anti-tubercular activity (MIC = 30.35 µM). Furthermore, 8e, 8 l, and 9d were found to be less toxic against human embryonic kidney, HEK 293 cell lines. Finally, a docking study was also performed using MTB DNA Gyrase (PDB ID: 5BS8) for the significantly active compound 8a to know the exact binding pattern within the active site of the target enzyme.

Screening Marine Natural Products for New Drug Leads against Trypanosomatids and Malaria.

Neglected Tropical Diseases (NTD) represent a serious threat to humans, especially for those living in poor or developing countries. Almost one-sixth of the world population is at risk of suffering from these diseases and many thousands die because of NTDs, to which we should add the sanitary, labor and social issues that hinder the economic development of these countries. Protozoan-borne diseases are responsible for more than one million deaths every year. Visceral leishmaniasis, Chagas disease or sleeping sickness are among the most lethal NTDs. Despite not being considered an NTD by the World Health Organization (WHO), malaria must be added to this sinister group. Malaria, caused by the apicomplexan parasite Plasmodium falciparum, is responsible for thousands of deaths each year. The treatment of this disease has been losing effectiveness year after year. Many of the medicines currently in use are obsolete due to their gradual loss of efficacy, their intrinsic toxicity and the emergence of drug resistance or a lack of adherence to treatment. Therefore, there is an urgent and global need for new drugs. Despite this, the scant interest shown by most of the stakeholders involved in the pharmaceutical industry makes our present therapeutic arsenal scarce, and until recently, the search for new drugs has not been seriously addressed. The sources of new drugs for these and other pathologies include natural products, synthetic molecules or repurposing drugs. The most frequent sources of natural products are microorganisms, e.g., bacteria, fungi, yeasts, algae and plants, which are able to synthesize many drugs that are currently in use (e.g. antimicrobials, antitumor, immunosuppressants, etc.). The marine environment is another well-established source of bioactive natural products, with recent applications against parasites, bacteria and other pathogens which affect humans and animals. Drug discovery techniques have rapidly advanced since the beginning of the millennium. The combination of novel techniques that include the genetic modification of pathogens, bioimaging and robotics has given rise to the standardization of High-Performance Screening platforms in the discovery of drugs. These advancements have accelerated the discovery of new chemical entities with antiparasitic effects. This review presents critical updates regarding the use of High-Throughput Screening (HTS) in the discovery of drugs for NTDs transmitted by protozoa, including malaria, and its application in the discovery of new drugs of marine origin.

Design, synthesis and α-amylase inhibitory activity of novel chromone derivatives.

Quercetin is one of the naturally occurring polyphenol flavonoid predominantly known for antidiabetic activity. In the present study, by considering the structural requirements, twenty two novel chromone derivatives (5-26) as α-amylase inhibitor were designed and subsequently in silico evaluated for drug likeness behavior. Designed compounds were synthesized, characterized by spectral analysis and finally evaluated for the inhibition of α-amylase activity by in vitro assay. Tested compounds exhibited significant to weak activity with IC50 range of 12-125µM. Among the tested compounds, analogues 5, 8, 12, 13, 15, 17 and 22 exhibited significant human α-amylase inhibitory activity with IC50 values <25µM, which can be further explored as anti-hyperglycemic agents. Putative binding mode of the significant and least active α-amylase inhibitors with the target enzyme was also explored by the docking studies.

Rational design, synthesis, anti-HIV-1 RT and antimicrobial activity of novel 3-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)-1-(piperazin-1-yl)propan-1-one derivatives.

In the present study, fifteen novel 3-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)-1-(piperazin-1-yl)propan-1-one (6a-o) derivatives were designed as inhibitor of HIV-1 RT using ligand based drug design approach and in-silico evaluated for drug-likeness properties. Designed compounds were synthesized, characterized and in-vitro evaluated for RT inhibitory activity against wild HIV-1 RT strain. Among the tested compounds, four compounds (6a, 6b, 6j and 6o) exhibited significant inhibition of HIV-1 RT (IC50⩽10µg/ml). All synthesized compounds were also evaluated for anti-HIV-1 activity as well as cytotoxicity on T lymphocytes, in which compounds 6b and 6l exhibited significant anti-HIV activity (EC50 values 4.72 and 5.45µg/ml respectively) with good safety index. Four compounds (6a, 6b, 6j and 6o) found significantly active against HIV-1 RT in the in-vitro assay were in-silico evaluated against two mutant RT strains as well as one wild strain. Further, titled compounds were evaluated for in-vitro antibacterial (Escherichia coli, Pseudomonas putida, Staphylococcus aureus and Bacillus cereus) and antifungal (Candida albicans and Aspergillus niger) activities.

Design, synthesis and in-vitro evaluation of novel tetrahydroquinoline carbamates as HIV-1 RT inhibitor and their antifungal activity.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) are vital class of drugs in treating HIV-1 infection, but drug resistance and toxicity drive the need for effective new inhibitors with potent antiviral activity, less toxicity and improved physicochemical properties. In the present study, twelve novel 1-(4-chlorophenyl)-2-(3,4-dihydroquinolin-1(2H)-yl)ethyl phenylcarbamate derivatives were designed as inhibitor of HIV-1 RT using the ligand based drug design approach and in-silico evaluated for drug-likeness properties. Designed compounds were synthesized, characterized and in-vitro evaluated for RT inhibitory activity against wild HIV-1 RT. Among these, four compounds (6b, 6i, 6j and 6l) exhibited significant inhibition of HIV-1 RT (IC50 ⩽ 20 µM). Among four compounds, most active compounds 6b and 6j inhibited the RT activity with IC50 8.12 and 5.42 µM respectively. Docking studies of compounds 6b and 6j were performed against wild HIV-1 RT in order to predict their putative binding mode with selected target. Further, cytotoxicity and anti-HIV activity of compounds 6b and 6j were evaluated on T lymphocytes (C8166 cells). All the synthesized compounds were also evaluated for antifungal activity against Candida albicans and Aspergillus niger fungal strains.

Design, synthesis of new ß-carboline derivatives and their selective anti-HIV-2 activity.

In the present study, a new series of ß-carboline derivatives were synthesized and evaluated for inhibition activity against both HIV-1 and HIV-2 strains. Among these reported analogues, surprisingly (1-phenyl-9H-pyrido[3,4-b]indol-3-yl)(4-p-tolylpiperazin-1-yl)methanone (7b), (4-(2-methoxyphenyl)piperazin-1-yl)(1-phenyl-9H-pyrido[3,4-b]indol-3-yl)methanone (7f), (4-(4-fluorophenyl)piperazin-1-yl)(1-phenyl-9H-pyrido[3,4-b]indol-3-yl)methanone (7k), (4-(2-fluorophenyl)piperazin-1-yl)(1-phenyl-9H-pyrido[3,4-b]indol-3-yl)methanone (7l) displayed selective inhibition of HIV-2 strain with EC50 values of 3.3, 3.2, 2.6 and 5.4µM, respectively, which are comparable with nucleoside reverse transcriptase inhibitors lamivudine and dideoxyinosine. As these analogues have not shown in vitro HIV-2 reverse transcriptase inhibition, it could be excluded as potential target for their specific anti-HIV-2 activity.

Synthesis, evaluation and molecular docking studies of amino acid derived N-glycoconjugates as antibacterial agents.

Six amino acid derived N-glycoconjugates of d-glucose were synthesized, characterized and tested for antibacterial activity against G(+)ve (Bacillus cereus) as well as G(-)ve (Escherichia coli and Klebsiella pneumoniae) bacterial strains. All the tested compounds exhibited moderate to good antibacterial activity against these bacterial strains. The results were compared with the antibacterial activity of standard drug Chloramphenicol, where results of A5 (Tryptophan derived glycoconjugates) against E. coli and A4 (Isoleucine derived glycoconjugates) against K. pneumoniae bacterial strains are comparable with the standard drug molecule. In silico docking studies were also performed in order to understand the mode of action and binding interactions of these molecules. The docking studies revealed that, occupation of compound A5 at the ATP binding site of subunit GyrB (DNA gyrase, PDB ID: 3TTZ) via hydrophobic and hydrogen bonding interactions may be the reason for its significant in vitro antibacterial activity.

Polyamine Metabolism for Drug Intervention in Trypanosomatids.

Neglected tropical diseases transmitted by trypanosomatids include three major human scourges that globally affect the world's poorest people: African trypanosomiasis or sleeping sickness, American trypanosomiasis or Chagas disease and different types of leishmaniasis. Different metabolic pathways have been targeted to find antitrypanosomatid drugs, including polyamine metabolism. Since their discovery, the naturally occurring polyamines, putrescine, spermidine and spermine, have been considered important metabolites involved in cell growth. With a complex metabolism involving biosynthesis, catabolism and interconversion, the synthesis of putrescine and spermidine was targeted by thousands of compounds in an effort to produce cell growth blockade in tumor and infectious processes with limited success. However, the discovery of eflornithine (DFMO) as a curative drug against sleeping sickness encouraged researchers to develop new molecules against these diseases. Polyamine synthesis inhibitors have also provided insight into the peculiarities of this pathway between the host and the parasite, and also among different trypanosomatid species, thus allowing the search for new specific chemical entities aimed to treat these diseases and leading to the investigation of target-based scaffolds. The main molecular targets include the enzymes involved in polyamine biosynthesis (ornithine decarboxylase, S-adenosylmethionine decarboxylase and spermidine synthase), enzymes participating in their uptake from the environment, and the enzymes involved in the redox balance of the parasite. In this review, we summarize the research behind polyamine-based treatments, the current trends, and the main challenges in this field.

Synthesis, biological evaluation and molecular modeling studies of modulated benzyloxychalcones as potential acetylcholinesterase inhibitors.

Acetylcholinesterase inhibitors (AChEIs) have become a significant target in the search for an efficient treatment of Alzheimer's disease. Chalcone-based compounds display a strong potency to hinder AChE. So, this study focused on the synthesis of a series of new chalcone derivatives with anti-cholinesterase potential and their structures were characterized based on spectroscopic methods including IR, 1H NMR, 13C NMR and HRMS. Chalcone derivatives were screened against AChE. Most of them exhibited potent inhibitory activity against AChE. Compound 11i showed the most potent activity toward acetylcholinesterase compared to the positive compound, Galantamine. Docking studies into the active site of the acetylcholinesterase enzyme ravealed the significant docking score of the synthesized compounds with docking score of -7.959 to -9.277 kcal/mol when compared to the co-crystallized ligand, Donepezil (-10.567 kcal/mol). The interaction's stability was further assessed using a conventional atomistic 100 ns dynamics simulation study, which revealed the conformational stability of representative compound 11i in the cavity of the acetylcholinesterase enzyme.Communicated by Ramaswamy H. Sarma.

In silico anti-viral assessment of phytoconstituents in a traditional (Siddha Medicine) polyherbal formulation - Targeting Mpro and pan-coronavirus post-fusion Spike protein.

Background and aim: Novel nature of the viral pathogen SARS-CoV-2 and the absence of standard drugs for treatment, have been a major challenge to combat this deadly infection. Natural products offer safe and effective remedy, for which traditional ethnic medicine can provide leads. An indigenous poly-herbal formulation, Kabasura Kudineer from Siddha system of medicine was evaluated here using a combination of computational approaches, to identify potential inhibitors against two anti-SARS-CoV-2 targets - post-fusion Spike protein (structural protein) and main protease (Mpro, non-structural protein). Experimental procedure: We docked 32 phytochemicals from the poly-herbal formulation against viral post-fusion Spike glycoprotein and Mpro followed by molecular dynamics using Schrodinger software. Drug-likeness analysis was performed using machine learning (ML) approach and pkCSM. Results: The binding affinity of the phytochemicals in Kabasura Kudineer revealed the following top-five bioactives: Quercetin > Luteolin > Chrysoeriol > 5-Hydroxy-7,8-Dimethoxyflavone > Scutellarein against Mpro target, and Gallic acid > Piperlonguminine > Chrysoeriol > Elemol > Piperine against post-fusion Spike protein target. Quercetin and Gallic acid exhibited binding stability in complexation with their respective viral-targets and favourable free energy change as revealed by the molecular dynamics simulations and MM-PBSA analysis. In silico predicted pharmacokinetic profiling of these ligands revealed appropriate drug-likeness properties. Conclusion: These outcomes provide: (a) potential mechanism for the anti-viral efficacy of the indigenous Siddha formulation, targeting Mpro and post-fusion Spike protein (b) top bioactive lead-molecules that may be developed as natural product-based anti-viral pharmacotherapy and their pleiotropic protective effects may be leveraged to manage co-morbidities associated with COVID-19.