Identification of novel inhibitor phytoconstituents for Influenza A H3N2: an in silico approach.

Influenza A virus subtype H3N2 is a highly infectious respiratory virus that is responsible for global seasonal flu epidemics. The current study was designed to investigate the antiviral activity of 150 phytocompounds of North Western Himalayas medicinal plants by molecular docking. Two target proteins of hemagglutinin of influenza virus A (PDB ID 4WE8) and Influenza virus H3N2 nucleoprotein - R416A mutant (PDB ID 7NT8) are selected for this study. Molecular docking was done by AutoDock vina tool, toxicity and drug-likeness prediction was done by protox II and Moleinspiration. MD simulation of best protein-ligand complexes was done by using Gromacs, version 2021.5. Molecular docking and toxicity data revealed that clicoemodin and rumexocide showed the best binding with both target proteins 4WEB & 7NT8. Clicoemodin showed the -7.5 KJ/mol binding energy with 4WE8 and 7NT8. Similarly, rumexoside showed the -7.6 KJ/mol binding energy with 4WE8 and -7.6 KJ/mol with 7NT8. Furthermore, Molecular dynamic simulation and MMPBSA binding free energy validated the stability of protein-ligand complexes. The current study suggested that clicoemodin and rumexocide are the promising inhibitors of H3N2 proteins hemagglutinin of influenza virus A and Influenza virus H3N2 nucleoprotein - R416A mutant, though there is further in vitro and in vivo validation is required.Communicated by Ramaswamy H. Sarma.

Antimicrobial potential of phytocompounds of Acorus calamus: in silico approach.

Medicinal plants are used from prehistoric time to cure various life-threatening bacterial diseases. Acorus calamus is an important medicinal plant widely used to cure gastrointestinal, respiratory, kidney and liver disorders. The objective of the current research was to investigate the interaction of major phytoconstituents of Acorus calamus with bacterial (6VJE) and fungal (1EA1) protein targets. Protein-ligand interactions were estimated using the AutoDock software, drug likeness was predicted by using the molinspiration server and toxicity was predicted with the swissADME and protox II servers. MD simulation of phytocompounds with the best profiles was done on the GROMACS software for 100 ns. Molecular docking results showed among all the selected major phytoconstituents, that ß-cadinene showed best binding interaction in complex with bacterial (6VJE) and fungal (1EA1) protein targets with binding energy -7.66 ± 0.1 and -7.73 ± 0.15 kcal mol-1, respectively. Drug likeness and toxicity predictions showed that ß-cadinene follows all rules of drug likeness and toxicity. MD simulation study revealed that ß-cadinene fit in binding pocket of bacterial and fungal targets and found to be stable throughout the duration of the simulation. Based on the observations from this in-silico study it is being proposed that ß-cadinene, a major phytocompound of Acorus calamus, can be considered for the treatment of bacterial and fungal infections since the study shows that it might be one of the compounds that contributes majorly to the plant's biological activity. This study needs in vitro and in vivo validation.Communicated by Ramaswamy H. Sarma.

Comparative docking studies of drugs and phytocompounds for emerging variants of SARS-CoV-2.

In the last three years, COVID-19 has impacted the world with back-to-back waves leading to devastating consequences. SARS-CoV-2, the causative agent of COVID-19, was first detected in 2019 and since then has spread to 228 countries. Even though the primary focus of research groups was diverted to fight against COVID-19, yet no dedicated drug has been developed to combat the emergent life-threatening medical conditions. In this study, 35 phytocompounds and 43 drugs were investigated for comparative docking analysis. Molecular docking and virtual screening were performed against SARS-CoV-2 spike glycoprotein of 13 variants using AutoDock Vina tool 1.5.6 and Discovery Studio, respectively, to identify the most efficient drugs. Selection of the most suitable compounds with the best binding affinity was done after screening for toxicity, ADME (absorption, distribution, metabolism and excretion) properties and drug-likeliness. The potential candidates were discovered to be Liquiritin (binding affinities ranging between -7.0 and -8.1 kcal/mol for the 13 variants) and Apigenin (binding affinities ranging between -6.8 and -7.3 kcal/mol for the 13 variants) based on their toxicity and consistent binding affinity with the Spike protein of all variants. The stability of the protein-ligand complex was determined using Molecular dynamics (MD) simulation of Apigenin with the Delta plus variant of SARS-CoV-2. Furthermore, Liquiritin and Apigenin were also found to be less toxic than the presently used drugs and showed promising results based on in silico studies, though, confirmation using in vitro studies is required. This in-depth comparative investigation suggests potential drug candidates to fight against SARS-CoV-2 variants. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03450-6.

Computational assessment of phytochemicals of medicinal plants from Mexico as potential inhibitors of Salmonella enterica efflux pump AcrB protein.

The AcrAB-TolC efflux pump (EP) confers multidrug resistance to Salmonella enterica, a major etiological agent of foodborne infections. Phytochemicals that inhibit the functions of AcrAB-TolC EP present ideal candidates for reversal of antibiotic resistance. Progressive technological advancements, have facilitated the development of computational methods that offer a rapid low-cost approach to screen and identify phytochemicals with inhibitory potential against EP. In this study, 71 phytochemicals derived from plants used for medicinal purposes in Mexico were screened for their potential as inhibitors of Salmonella AcrB protein using in silico approaches including molecular docking and molecular dynamics (MD) simulation. Consequently, naringenin, 5-methoxypsoralen, and licarin A were identified as candidate inhibitors of AcrB protein. The three phytochemicals bound distal/deep pocket (DP) and hydrophobic trap (HPT) residues of AcrB protein critical for interactions with inhibitors, with estimated binding free energies of -95.5 kJ/mol, -97.4 kJ/mol, and -143.8 kJ/mol for naringenin, 5-methoxypsoralen, and licarin A, respectively. Data from the 50 ns MD simulation study revealed stability of the protein-ligand complex and alterations in the AcrB protein DP conformation upon binding of phytochemicals to the DP and HPT regions. Based on the estimated binding free energy and interactions with three out of five residues lining the hydrophobic trap, licarin A demonstrated the highest inhibitory potential, supporting its further application as a candidate for overcoming drug resistance in pathogens. Communicated by Ramaswamy H. Sarma.

Antibacterial Potential of Bacopa monnieri (L.) Wettst. and Its Bioactive Molecules against Uropathogens-An In Silico Study to Identify Potential Lead Molecule(s) for the Development of New Drugs to Treat Urinary Tract Infections.

Urinary tract infections (UTIs) are becoming more common, requiring extensive protection from antimicrobials. The global expansion of multi-drug resistance uropathogens in the past decade emphasizes the necessity of newer antibiotic treatments and prevention strategies for UTIs. Medicinal plants have wide therapeutic applications in both the prevention and management of many ailments. Bacopa monnieri is a medicinal plant that is found in the warmer and wetlands regions of the world. It has been used in Ayurvedic systems for centuries. The present study aimed to investigate the antibacterial potential of the extract of B. monnieri leaves and its bioactive molecules against UTIs that are caused by Klebsiella pneumoniae and Proteus mirabilis. This in vitro experimental study was conducted by an agar well diffusion method to evaluate the antimicrobial effect of 80% methanol, 96% ethanol, and aqueous extracts of B. monnieri leaves on uropathogens. Then, further screening of their phytochemicals was carried out using standard methods. To validate the bioactive molecules and the microbe interactions, AutoDock Vina software was used for molecular docking with the Klebsiella pneumoniae fosfomycin resistance protein (5WEW) and the Zn-dependent receptor-binding domain of Proteus mirabilis MR/P fimbrial adhesin MrpH (6Y4F). Toxicity prediction and drug likeness were predicted using ProTox-II and Molinspiration, respectively. A molecular dynamics (MD) simulation was carried out to study the protein ligand complexes. The methanolic leaves extract of B. monnieri revealed a 22.3 mm ± 0.6 mm to 25.0 mm ± 0.5 mm inhibition zone, while ethanolic extract seemed to produce 19.3 mm ± 0.8 mm to 23.0 mm ± 0.4 mm inhibition zones against K. pneumoniae with the use of increasing concentrations. In the case of P. mirabilis activity, the methanolic extracts showed a 21.0 mm ± 0.8 mm to 24.0 mm ± 0.6 mm zone of inhibition and the ethanol extract produced a 17.0 mm ± 0.9 mm to 23.0 mm ± 0.7 mm inhibition zone with increasing concentrations. Carbohydrates, flavonoids, saponin, phenolic, and terpenoid were common phytoconstituents identified in B. monnieri extracts. Oroxindin showed the best interactions with the binding energies with 5WEW and 6Y4F, -7.5 kcal/mol and -7.4 kcal/mol, respectively. Oroxindin, a bioactive molecule, followed Lipinski's rule of five and exhibited stability in the MD simulation. The overall results suggest that Oroxindin from B. monnieri can be a potent inhibitor for the effective killing of K. pneumoniae and P. mirabilis. Additionally, its safety has been established, indicating its potential for future drug discovery and development in the treatment for UTIs.

An In Silico Investigation to Explore Anti-Cancer Potential of Foeniculum vulgare Mill. Phytoconstituents for the Management of Human Breast Cancer.

Breast cancer is one of the most prevalent cancers in the world. Traditionally, medicinal plants have been used to cure various types of diseases and disorders. Based on a literature survey, the current study was undertaken to explore the anticancer potential of Foeniculum vulgare Mill. phytoconstituents against breast cancer target protein (PDB ID: 6CHZ) by the molecular docking technique. Molecular docking was done using Autodock/vina software. Toxicity was predicted by the Protox II server and drug likeness was predicted by Molinspiration. 100 ns MD simulation of the best protein-ligand complexes were done using the Amber 18 tool. The present molecular docking investigation has revealed that among the 40 selected phytoconstituents of F. vulgare, α-pinene and D-limonene showed best binding energy (-6 and -5.9 kcal/mol respectively) with the breast cancer target. α-Pinene and D-limonene followed all the parameters of toxicity, and 100 ns MD simulations of α-pinene and D-limonene complexes with 6CHZ were found to be stable. α-Pinene and D-limonene can be used as new therapeutic agents to cure breast cancer.

Methylxanthines as Potential Inhibitor of SARS-CoV-2: an In Silico Approach.

The aim of the present study was to test the binding affinity of methylxanthines (caffeine/theine, methylxanthine, theobromine, theophylline and xanthine) to three potential target proteins namely Spike protein (6LZG), main protease (6LU7) and nucleocapsid protein N-terminal RNA binding domain (6M3M) of SARS-CoV-2. Proteins and ligand were generated using AutoDock 1.5.6 software. Binding affinity of methylxanthines with SARS-CoV-2 target proteins was determined using Autodock Vina. MD simulation of the best interacting complexes was performed using GROMACS 2018.3 (in duplicate) and Desmond program version 2.0 (academic version) (in triplicate) to study the stabile interaction of protein-ligand complexes. Among the selected methylxanthines, theophylline showed the best binding affinity with all the three targets of SARS-CoV-2 (6LZG - 5.7 kcal mol-1, 6LU7 - 6.5 kcal mol-1, 6M3M - 5.8 kcal mol-1). MD simulation results of 100 ns (in triplicate) showed that theophylline is stable in the binding pockets of all the selected SARS-CoV-2 proteins. Moreover, methylxanthines are safer and less toxic as shown by high LD50 value with Protox II software as compared to drug chloroquine. This research supports the use of methylxanthines as a SARS-CoV-2 inhibitor. It also lays the groundwork for future studies and could aid in the development of a treatment for SARS-CoV-2 and related viral infections. Supplementary Information: The online version contains supplementary material available at 10.1007/s40495-021-00276-3.

Phytoconstituents of traditional Himalayan Herbs as potential inhibitors of Human Papillomavirus (HPV-18) for cervical cancer treatment: An In silico Approach.

Human papillomavirus (HPV) induced cervical cancer is becoming a major cause of mortality in women. The present research aimed to identify the natural inhibitors of HPV-18 E1 protein (1R9W) from Himalayan herbs with lesser toxicity and higher potency. In this study, one hundred nineteen phytoconstituents of twenty important traditional medicinal plants of Northwest Himalayas were selected for molecular docking with the target protein 1R9W of HPV-18 E1 Molecular docking was performed by AutoDock vina software. ADME/T screening of the bioactive phytoconstituents was done by SwissADME, admetSAR, and Protox II. A couple of best protein-ligand complexes were selected for 100 ns MD simulation. Molecular docking results revealed that among all the selected phytoconstituents only thirty-five phytoconstituents showed the binding affinity similar or more than the standard anti-cancer drugs viz. imiquimod (-6.1 kJ/mol) and podofilox (-6.9 kJ/mol). Among all the selected thirty-five phytoconstituents, eriodictyol-7-glucuronide, stigmasterol, clicoemodin and thalirugidine showed the best interactions with a docking score of -9.1, -8.7, -8.4, and -8.4 kJ/mol. Based on the ADME screening, only two phytoconstituents namely stigmasterol and clicoemodin selected as the best inhibitor of HPV protein. MD simulation study also revealed that stigmasterol and clicoemodin were stable inside the binding pocket of 1R9W, Stigmasterol and clicoemodin can be used as a potential investigational drug to cure HPV infections.

Synthesis and characterization of novel combretastatin analogues of 1,1-diaryl vinyl sulfones, with antiproliferative potential via in-silico and in-vitro studies.

Novel 1,1-diaryl vinyl-sulfones analogues of combretastatin CA-4 were synthesized via Suzuki-Miyaura coupling method and screened for in-vitro antiproliferative activity against four human cancer cell lines: MDA-MB 231(breast cancer), HeLa (cervical cancer), A549 (lung cancer), and IMR-32 (neuroblast cancer), along with a normal cell line HEK-293 (human embryonic kidney cell) by employing 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay. The compounds synthesised had better cytotoxicity against the A549 and IMR-32 cell lines compared to HeLa and MDA-MB-231 cell lines. The synthesized compounds also showed significant activity on MDA-MB-231 cancer cell line with IC50 of 9.85-23.94 µM, and on HeLa cancer cell line with IC50 of 8.39-11.70 µM relative to doxorubicin having IC50 values 0.89 and 1.68 µM respectively for MDA-MB-231 and HeLa cell lines. All the synthesized compounds were not toxic to the growth of normal cells, HEK-293. They appear to have a higher binding affinity for the target protein, tubulin, PDB ID = 5LYJ (beta chain), relative to the reference compounds, CA4 (- 7.1 kcal/mol) and doxorubicin (- 7.2 kcal/mol) except for 4E, 4M, 4N and 4O. The high binding affinity for beta-tubulin did not translate into enhanced cytotoxicity but the compounds (4G, 4I, 4J, 4M, 4N, and 4R, all having halogen substituents) that have a higher cell permeability (as predicted in-silico) demonstrated an optimum cytotoxicity against the tested cell lines in an almost uniform manner for all tested cell lines. The in-silico study provided insight into the role that cell permeability plays in enhancing the cytotoxicity of this class of compounds and as potential antiproliferative agents.

Phytocompounds from Himalayan Medicinal Plants as Potential Drugs to Treat Multidrug-Resistant Salmonella typhimurium: An In Silico Approach.

Medicinal plants can be used as natural therapeutics to treat diseases in humans. Enteric bacteria possess efflux pumps to remove bile salts from cells to avoid potential membrane damage. Resistance to bile and antibiotics is associated with the survival of Salmonella enterica subspecies enterica serovar Typhimurium (S. typhimurium) within a host. The present study aimed to investigate the binding affinity of major phytocompounds derived from 35 medicinal plants of the North Western Himalayas with the RamR protein (PDB ID 6IE9) of S. typhimurium. Proteins and ligands were prepared using AutoDock software 1.5.6. Molecular docking was performed using AutoDock Vina and MD simulation was performed at 100 ns. Drug likeness and toxicity predictions of hit phytocompounds were evaluated using molinspiration and ProTox II online servers. Moreover, docking, drug likeness, and toxicity results revealed that among all the selected phytocompounds, beta-sitosterol exhibited the most efficacious binding affinity with RamR protein (PDB ID 6IE9) and was nontoxic in nature. MD simulation data revealed that beta-sitosterol in complex with 6IE9 can be used as an antimicrobial. Furthermore, beta-sitosterol is stable in the binding pocket of the target protein; hence, it can be further explored as a drug to inhibit resistance-nodulation-division efflux pumps.

Structure based design, stability study and synthesis of the dinitrophenylhydrazone derivative of the oxidation product of lanosterol as a potential P. falciparum transketolase inhibitor and in-vivo antimalarial study.

The growing resistance to the current antimalarial drugs in the absence of a vaccine can be effectively tackled by identifying new metabolic pathways that are essential to the survival of the malaria parasite and developing new drugs against them. Triterpenes and steroids are the most abundant group of natural products with a great variety of biological activities. However, lanosterol is not known to possess any significant biological activity. In this study the binding and interactions of a dinitrophenyl hydrazine (DNP) derivative of lanosterol, LAN (a derivative that incorporates a substantially polar moiety into the steroid) with P. falciparum transketolase was studied by molecular docking and MD simulation with the view to exploit the DNP derivative as a lead in antimalarial chemotherapy development considering that the P. falciparum transketolase (PfTk) is a novel target in antimalarial chemotherapy. The enzyme catalyses the production of ribose sugars needed for nucleic acid synthesis; it lacks a three-dimensional (3D) structure necessary for docking because it is difficult to obtain a crystalline form. A homology model of PfTk was constructed using Saccharomyces cerevisiae transketolase (protein data bank ID of 1TRK) as the template. The compound was observed to have Free Energy of Binding higher than that of the cofactor of the protein (Thiamine Pyrophosphate, TPP) and a synthetic analog (SUBTPP) used as reference compounds after MD Simulation. The compound was synthesized in a two-step, one-pot reaction, utilizing a non-acidic and mild oxidant to oxidize the lanosterol in order to avoid the rearrangement that accompanies the oxidation of sterols using acidic oxidants. The LAN was characterized using IR spectroscopy and NMR experiments and tested in-vivo for its antimalarial chemo suppression using a murine model with Chloroquine as a standard. The LAN at a concentration of 25 mg/kg was found to have a comparable activity with Chloroquine at 10 mg/kg and no mortality was observed among the test animals 24 days post drug administration showing that the compound indeed has potential as an antimalarial agent and a likely inhibitor of PfTk considering that there is a strong agreement between the in-silico results and biological study. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-021-00097-8.

Tryptanthrin from microwave-assisted reduction of isatin using solid-state-supported sodium borohydride: DFT calculations, molecular docking and evaluation of its analgesic and anti-inflammatory activity.

Tryptanthrin is a potent natural alkaloid with good in vitro pharmacological properties. Herein, we report the synthesis of the compound via a new method involving the reduction of isatin with solid-state-supported sodium borohydride under microwave irradiation. The title compound has been tested for its analgesic and anti-inflammatory activity. The results showed that tryptanthrin dose dependently inhibits oedema and pain formation in all the models used. The agent also exhibited significant higher effects in its anti-inflammatory and analgesic activities better than positive drugs (aspirin and indomethacin) being currently used in the treatment and in the management of acute and chronic forms of pain and inflammatory disorders. The inhibitory potential of the compound was investigated by molecular docking using the software AutoDock Vina. The docking results were used to better rationalize the action and prediction of the binding affinity of tryptanthrin. Density Functional Theory (DFT) calculations at the B3LYP/6-311++G (2df, 2pd) level of theory showed that compared to ascorbic acid, tryptanthrin shows higher antioxidant activity which may be improved upon by functionalizing the aromatic core to enhance its solubility in polar solvents. The calculated electronic and thermodynamic properties obtained for tryptanthrin compete well with the standard ascorbic acid.

Computational screening of phytochemicals from three medicinal plants as inhibitors of transmembrane protease serine 2 implicated in SARS-CoV-2 infection.

Background: SARS-CoV-2 infection or COVID-19 is a major global public health issue that requires urgent attention in terms of drug development. Transmembrane Protease Serine 2 (TMPRSS2) is a good drug target against SARS-CoV-2 because of the role it plays during the viral entry into the cell. Virtual screening of phytochemicals as potential inhibitors of TMPRSS2 can lead to the discovery of drug candidates for the treatment of COVID-19. Purpose: The study was designed to screen 132 phytochemicals from three medicinal plants traditionally used as antivirals; Zingiber officinalis Roscoe (Zingiberaceae), Artemisia annua L. (Asteraceae), and Moringa oleifera Lam. (Moringaceae), as potential inhibitors of TMPRSS2 for the purpose of finding therapeutic options to treat COVID-19. Methods: Homology model of TMPRSS2 was built using the ProMod3 3.1.1 program of the SWISS-MODEL. Binding affinities and interaction between compounds and TMPRSS2 model was examined using molecular docking and molecular dynamics simulation. The drug-likeness and ADMET (absorption, distribution, metabolism, excretion, and toxicity) properties of potential inhibitors of TMPRSS2 were also assessed using admetSAR web tool. Results: Three compounds, namely, niazirin, quercetin, and moringyne from M. oleifera demonstrated better molecular interactions with binding affinities ranging from -7.1 to -8.0 kcal/mol compared to -7.0 kcal/mol obtained for camostat mesylate (a known TMPRSS2 inhibitor), which served as a control. All the three compounds exhibited good drug-like properties by not violating the Lipinski rule of 5. Niazirin and moringyne possessed good ADMET properties and were stable in their interactions with the TMPRSS2 based on the molecular dynamics simulation. However, the ADMET tool predicted the potential hepatotoxic and mutagenic effects of quercetin. Conclusion: This study demonstrated the potentials of niazirin, quercetin, and moringyne from M. oleifera, to inhibit the activities of human TMPRSS2, thus probably being good candidates for further development as new drugs for the treatment or management of COVID-19.

UHPLC/GC-TOF-MS metabolomics, MTT assay, and molecular docking studies reveal physostigmine as a new anticancer agent from the ethyl acetate and butanol fractions of Kigelia africana (Lam.) Benth. fruit extracts.

Kigelia africana plant is widely used as a herbal remedy in preventing the onset and the treatment of cancer-related infections. With the increase in the research interest of the plant, the specific chemical compound or metabolite that confers its anticancer properties has not been adequately investigated. The ethyl acetate and butanol fractions of the fruit extracts were evaluated by 2-(4,5-dimethylthiazol-2-yl)-3,5-diphenyl-2H-tetrazolium bromide assay against four different cell lines, with the ethyl acetate fraction having inhibition concentration values of 0.53 and 0.42 µM against Hep G2 and HeLa cells, respectively. More than 235 phytoconstituents were profiled using UHPLC-TOF-MS, while more than 15 chemical compounds were identified using GC-MS from the fractions. Molecular docking studies revealed that physostigmine, fluazifop, dexamethasone, sulfisomidine, and desmethylmirtazapine could favorably bind at higher binding energies of -8.3, -8.6, -8.2, and -8.1 kcal/mol, respectively, better than camptothecin with a binding energy of -7.9 kcal/mol. The results of this study showed that physostigmine interacted well with topoisomerase IIα and had a high score of pharmacokinetic prediction using absorption, distribution, metabolism, excretion, and toxicity profiles, thereby suggesting that drug design using physostigmine as a base structure could serve as an alternative against the toxic side effects of doxorubicin and camptothecin.

Supramolecular architecture in 1:1 cocrystal of N-carbamothioylacetamide and N,N'-thiocarbonyldiacetamide from the attempted synthesis of 1,3-diacetyl-2-thioxoimidazolidine-4,5-dione (a thioparabanic acid derivative).

An attempt to synthesize thioparabanic acid as precursor to other fused heterocyclic compounds, by a microwave assisted multistep one-pot reaction yielded a co-crystal of N-carbamothioylacetamide (NCTA) and N,N'-thiocarbonyldiacetamide (NNTCA) which is being reported in this paper. The structure of N-carbamothioylacetamide and N,N'-thiocarbonyldiacetamide from the attempted synthesis of 1,3-diacetyl-2-thioxoimidazolidine-4,5-dione, C5H8N2O2S.C3H6N2OS, has triclinic (P-1) symmetry. It is of interest with respect to biological application. The structure displays inter- and intra-molecular hydrogen bonding through -C=O···H interactions. Similarly, -C=S···H hydrogen bonding interactions are present, providing additional intermolecular stability to the co-crystal. For application as a potential drug candidate, a density functional theory (DFT) simulation of the antioxidant activities of the co-crystal and its individual components (NCTA and NNTCA) has been performed. The computed redox potentials indicate that the study compounds show comparable antioxidant activities with ascorbic acid (AA) for a one electron transfer process. Meanwhile, for a two-electron process, AA showed significant antioxidant advantage over the titled compound.

De novo design of thioredoxin reductase-targeted heterometallic titanocene-gold compounds of chlorambucil for mechanistic insights into renal cancer.

Here we report the design and synthesis of a chlorambucil-alkynyl (CHL-CCH) ligand, mononuclear gold(i) complex K[(CHL-CC)AuCl], 1, and heteronuclear complex (CHL-CC)Au(µ2-η2-CS3)Ti(η5-Cp)2, 2 for renal cancer. Complex 2 is significantly more cytotoxic than complex 1 and cisplatin against renal cancer cells with a high selectivity index value. The mechanism of action of these complexes against renal cancer cells was studied in detail by experimental and computational methods.

Experimental and theoretical investigations of cyclometalated ruthenium(ii) complex containing CCC-pincer and anti-inflammatory drugs as ligands: synthesis, characterization, inhibition of cyclooxygenase and in vitro cytotoxicity activities in various cancer cell lines.

The new cyclometalated ruthenium(ii) complex, [Ru(CCC-Nap)(Ibu)(PTA)] was designed and synthesized using ibuprofen (Ibu), 1,3,5-triaza-7-phosphaadamantane (PTA) and CCC-pincer containing naproxen moiety (CCC-Nap) as ligands. The compounds were fully characterized by elemental analysis, FT-IR, multinuclear (1H, 13C, and 31P) NMR spectroscopy, and electrospray ionization mass spectrometry. The cytotoxicity of the newly synthesized Ru(ii) complex was found to be low, and the complex was about twice as active as cisplatin with IC50 values in the range of 0.9-1.32 µM for both MCF-7 and MDA-MB-231 cell lines. Cyclooxygenase (COX) inhibition studies revealed that the Ru(ii) complex displayed strong interactions with COX-2, about 16 and 5 times more than free Ibu and CCC-Nap ligands, respectively. The Ru(ii) complex improved the production of reactive oxygen species (ROS) by 10.7 fold compared to the control (H2O2 as a positive control) in MCF-7 cells. Quantum chemical calculations gave more insights into the geometry and electronic properties of the novel Ru(ii) complex, while molecular docking provided theoretical information on the interactions of Ru(ii) complex with human cyclooxygenase-2 (COX-2) and the results were compared with those of the interactions of the free ligands with COX-2.

11-(4-Meth-oxy-phen-yl)-3,3-dimethyl-2,3,4,5,10,11-hexa-hydro-1H-dibenzo[b,e][1,4]diazepin-1-one monohydrate.

In the title compound, C(22)H(24)N(2)O(2)·H(2)O, the co-crystallized water mol-ecule inter-acts with the N and O atoms of the mol-ecule through O(w)-H⋯N, O(w)-H⋯O(meth-yl) and N-H⋯O(w) hydrogen-bonding inter-actions. These hydrogen bonds, along with the inter-molecular N-H⋯O=C hydrogen-bonding inter-actions, connect the mol-ecules into a three-dimensional network. The dihedral angle between the two aromatic rings is 65.46 (10)°.