Medicinal Chemistry - Volume 11, Issue 7, 2015

Microbe-host signalling is now a well accepted concept and an intensively studied research field. Although some of the observed bacterial phenotypes are atributed to host-recognition and interkingdom signalling, most of them are not relying on a proved molecular mechanism. Recent progress revealed some recognition and signalling pathways for host molecules in bacterial cells, which try to explain their modulatory effect on growth and virulence. Since the current knowledge on the field is poor and debatable, the purpose of this paper is to review and discuss the research performed in order to elucidate the ways by which microbial cells recognize and decode the host molecule signals.

Every year, cancer takes the life of millions of people. Conventional treatments have produced unsatisfactory results for some types of cancer, and the side effects are extensive, leading to a shift in the focus of treatment towards alternative medicines. Indeed, medicinal plants have long been investigated by scientists for their anti-cancer properties. Some phytochemicals that are important active constituents of plants, including catechins, ursolic acid, silymarin, glycyrrhizin, ellagic acid, gallic acid and various types of flavonoids, have shown promise in future cancer management. The current review covers various aspects of cancer treatment based on medicinal plants at molecular level and sheds light on their structures and modes of action.

A series of secondary amines combining monoterpenoid and aminoadamantane moieties have been synthesized. Their cytotoxic activity against human cancer cells CEM-13, MT-4, and U-937 has been studied for the first time. Most of the obtained compounds exhibited a significant cytotoxic activity with the median cytotoxic dose (CTD50) ranging from 6 to 84 μM. The most promising results were obtained for compound 2b which was synthesized from 1-aminoadamantane and (-)-myrtenal and revealed a high activity against all tumor lines used (CTD50 = 12÷21 μM) along with low toxicity with respect to MDCK cells (CTD50 = 1500 μM). The synthesized amines do not exert the genotoxic effect on cells of the biosensor strain based on recombinant E. coli cells bearing the pRAC-gfp plasmid.

A facile and atom-economical boric acid catalyzed direct amidation without any coupling agents for the preparation of Suberoylanilide Hydroxamic Acid (SAHA) and SAHA-based inhibitors targeting anti-proliferation of cancer cells is described. It is applicable to the preparation of SAHAbased inhibitors having an unprotected hydroxyl group in the phenyl ring without the need of the protection. The in-vitro assays data indicate that the nature and the position of the substituents (activating and/or deactivating) in the capping group (phenyl ring) of SAHA-based inhibitors synthesized in this study have a vital impact on the potency of anti-proliferative activity against cancer cells. With low toxicity toward the normal cells, a number of synthesized SAHA-based inhibitors with two substituents in the phenyl ring possess higher antiproliferative activity than SAHA and Cisplatin toward six studied cancer cell lines: A375 human skin cancer cells, A549 human lung cancer cells, MGC80-3 human gastric cancer cells, H460 human lung cancer cells, H1299 human lung cancer cells, and HepG2 human liver cancer cells. Cisplatin is a common chemotherapeutic drug with high cytotoxicity for a variety of cancer treatments. The inhibitors provided in this study might signify future therapeutic drugs for cancer treatment.

Diagnosis of tumour hypoxia is an important aspect in determining the course of tumour therapy. In this study, we developed a novel imaging agent, 99mTcethylenedicysteine- bis-misonidazole (99mTc-EC-MISO), for diagnosing tumour hypoxia. We used 2-nitroimidazole as a reactant to synthesize the amino derivative of misonidazole (MISO) in the first step and then conjugated the di-amino derivative of MISO to the chelating agent ethylenedicysteine (EC) for labelling 99mTc in the second step. 99mTc-pertechnetate (99mTcO4 -) was reduced by tin chloride (SnCl2) for radiolabeling. The radiochemical purity was up to 94%. Tissue biodistribution and SPECT/CT imaging studies were conducted on subcutaneous gliomal tumour-bearing mice. The tumour-to-muscle ratio in the 99mTc-EC-MISO group increased with time, up to 4.6 at 4 h after injection. SPECT/CT imaging confirmed that the tumours could be visualized clearly with 99mTc-EC-MISO at 2 h. By introducing a second 2-nitroimidazole redox centre, an apparent hypoxic accumulation of this novel 99mTc-labeled imaging agent in the tumour was observed.

A series of 26 quaternary ammonium pyridoxine derivatives were synthesized and their cytotoxicity and antibacterial activities against clinically relevant bacterial strains were tested in vitro. The antibacterial activity of mono-ammonium salts increased with the rise of the lipophilicity and compound 3,3,5-trimethyl-8,8-dioctyl-1,7,8,9-tetrahydro-[1,3]dioxino[5,4-d]pyrrolo[3,4-b]pyridin-8- ium chloride (2d) reaches a maximum among them. Bis-ammonium salt of pyridoxine 4 with two dimethyloctylamine groups also demonstrated high antibacterial activity despite lower lipophilicity. The results of MTT assay indicated that HEK 293 cells were more sensitive than HSF to quaternary ammonium pyridoxine derivatives. Compounds 2d and 4 did not induce the damage of the DNA and might be of interest in the development of new antimicrobials.

The diisopentenyloxy quinolobactin derivative 3-methylbut-2-enyl-4-methoxy-8-[(3- methylbut-2-enyl)oxy] quinoline-2-carboxylate, also named as Ppc-1, has been initially isolated from the fruiting bodies of the cellular slime mold Polysphondylium pseudo-candidum. Given that few data are available in the literature concerning the biological properties of this compound, this study was undertaken to evaluate its antibacterial and anti-inflammatory properties. Ppc-1 exerted antibacterial activity on the Gram negative periodontopathogen Porphyromonas gingivalis, while it had no such effect on the other bacterial species tested. The antibacterial activity of Ppc-1 appeared to result from its ability to permeate the cell membrane. Using the U937-3xΚB-LUC human monocytic cell line, Ppc-1 was found to dose-dependently inhibit the lipopolysaccharide-induced NF-ΚB activation, a signaling pathway that has been associated with inflammatory mediator secretion. In conclusion, Ppc-1, by exhibiting a dual mode of action including antibacterial and anti-inflammatory activities, may represent a promising targeted therapeutic agent for periodontal diseases.

We showed di[3,5-diacetyl-1,2,4-triazolbis(4-cyclohexylthiosemicarbazonato) platinum( II)] complex, (W8), endowed with important antitumor properties. Here, we analysed whether W8 can affect human bone marrow-derived Mesenchymal Stem Cells, (hMSCs), involved in tissue repair, immunomodulatory properties and also capacity for homing to injure-tumor sites in ovarian cancer. Specifically, we analysed the effect of W8 on cell proliferation, response to scratch, and whether copper-derived cellular mechanism is used by this platinum(II) complex being studied. Results showed that W8 causes a significant inhibition of cell proliferation at μM concentration. This effect is directly related to the alteration of cytoskeletal proteins and inhibition of the response to scratch induced by the presence of foetal bovine serum. This strongly supports the notion of W8 triggers the energetic metabolism of hMSCs and adds an extra support by the results showing W8 relationship with the cellular copper ions. W8, acting in hMSCs, regulates in addition the inhibition of cell proliferation, the inhibition of tumor angiogenesis and metastasis.

Psychotic disorders are complex and caused by interplay of genetic and environmental factors. Influenza is a common infectious disease in humans, and it has been suggested that maternal influenza is an estimated risk factor for psychotic disorders, especially for schizophrenia. In view of conflicting results of this association in literature, we performed the strict meta-analysis to examine whether maternal influenza is a risk factor for psychosis in the children. Four ecological studies and three birth cohort studies were included in our meta-analysis. It has been observed that the Risk Ratio (RR) of maternal influenza on psychosis is 1.062 (95% Confidence Interval (CI) = 1.004-1.123) for the analysis of ecological studies and the RR is 1.564(95%CI=1.051-2.324) for the analysis of birth cohort studies. Furthermore, a survey of pregnant women and fetus’ health in Nanjing of China indicated that only 1.5% of women received the influenza vaccine before pregnancy, 0.4% received it during pregnancy, and 5.1% were willing to receive the influenza vaccine if necessary. These results showed that gestational influenza could increase mental disorders risks in adult offspring besides its established harms for gravidas. Results suggest it might be effective to increase attention to gravidas to protect them from influenza infection through encouragement of vaccinations.

Oxime K203 seems to be the most promising oxime in case of reactivation of tabuninhibited acetylcholinesterase (AChE). Although it was originally developed for treatment of tabun intoxications, it is able to reactivate cholinesterases inhibited by other nerve agents. This study is aimed at the evaluation of its potency in vitro against other nerve agents. For this purpose, sarin, tabun, cyclosarin, soman, VX, Russian VX and DFP were selected as members of the nerve agent family to check its universality. At high concentrations (10-3 M), oxime K203 reached promising reactivation activity. At low concentrations, relevant for human use (10-5 M), promising reactivation potency was obtained only with tabun. In conclusion, oxime K203 reactivates other nerve agents-inhibited cholinesterases, however its broad-spectrum reactivation is limited at high, for human not attainable, concentrations only.

Objective: Drug resistance from affordable drugs has increased the number of deaths from malaria globally. This problem has raised the requirement to design new drugs against multidrugresistant Plasmodium falciparum parasite. Methods: In the current project, we have focused on four important proteins of Plasmodium falciparum and used them as receptors against a dataset of four anti-malarial drugs. In silico analysis of these receptors and ligand dataset was carried out using Autodock 4.2. A pharmacophore model was also established using Ligandscout. Results: Analysis of docking experiments showed that all ligands bind efficiently to four proteins of Plasmodium falciparum. We have used ligand-based pharmacophore modeling and developed a pharmacophore model that has three hydrophobic regions, two aromatic rings, one hydrogen acceptor and one hydrogen donor. Using this pharmacophore model, we have screened a library of 50,000 compounds. The compounds that shared features of our pharmacophore model and exhibited interactions with the four proteins of our receptors dataset are short-listed. Conclusion: As there is a need of more anti-malarial drugs, therefore, this research will be helpful in identifying novel anti-malarial drugs that exhibited bindings with four important proteins of Plasmodium falciparum. The hits obtained in this study can be considered as useful leads in anti-malarial drug discovery.

A series of palladium complexes with 2,2’-bipyridine and 1-(substituted benzyl) azetidine- 3, 3-dicarboxylates as ligands were synthesized and characterized by IR, 1H-NMR, ESI-MS spectra and elemental analysis. The in vitro cytotoxicity assays were carried out against A549, HCT-116, HepG-2 and SGC7901 cancer cell lines. The result showed that most of the complexes possessed moderate antiproliferative activity against HCT-116, HepG-2 and SGC7901 cell lines. Complex 12 (with 2,2’-bipyridine and 1-(3-methoxylbenzyl)azetidine-3,3-dicarboxylate as ligand) was the most potent antitumor agent among all thirteen complexes, which showed comparable or better cytotoxicity against all four tested cancer cell lines than carboplatin. The interaction between complex 12 and pET22b plasmid DNA was investigated by agarose gel electrophoresis, and the result of the study showed that complex 12 had no obvious interaction with the plasmid DNA.