Letters in Drug Design & Discovery - Volume 16, Issue 5, 2019

Aims: The aim of this review is to survey the recent progress made in developing the nanoparticles as antifungal agents especially the nano-based formulations being exploited for the management of Candida infections. Discussion: In the last few decades, there has been many-fold increase in fungal infections including candidiasis due to the increased number of immunocompromised patients worldwide. The efficacy of available antifungal drugs is limited due to its associated toxicity and drug resistance in clinical strains. The recent advancements in nanobiotechnology have opened a new hope for the development of novel formulations with enhanced therapeutic efficacy, improved drug delivery and low toxicity. Conclusion: Metal nanoparticles have shown to possess promising in vitro antifungal activities and could be effectively used for enhanced and targeted delivery of conventionally used drugs. The synergistic interaction between nanoparticles and various antifungal agents have also been reported with enhanced antifungal activity.

Aim: The present review aims to explore the development of novel antifungal agents, such as pharmacology, pharmacokinetics, spectrum of activity, safety, toxicity and other aspects that involve drug-drug interactions of the azole antifungal agents. Introduction: Fungal infections in critically ill and immune-compromised patients are increasing at alarming rates, caused mainly by Candida albicans an opportunistic fungus. Despite antifungal annihilators like amphotericin B, azoles and caspofungin, these infections are enormously increasing. The unconventional increase in such patients is a challenging task for the management of antifungal infections especially Candidiasis. Moreover, problem of toxicity associated with antifungal drugs on hosts and rise of drug-resistance in primary and opportunistic fungal pathogens has obstructed the success of antifungal therapy. Conclusion: Hence, to conflict these problems new antifungal agents with advanced efficacy, new formulations of drug delivery and novel compounds which can interact with fungal virulence are developed and used to treat antifungal infections.

Background: The emergence of fungal resistance to commercial drugs has been observed, and because of that, research with natural products have been performed with the aim of obtaining bioactive compounds. Objective: Evaluate the chemical composition and antifungal activity of the ethanolic extract of Costus cf. arabicus L leaves (EECAL) over strains of the genus Candida, as well as its inhibitory potential over yeast virulence. Methods: The composition of EECAL was analyzed through High Performance Liquid Chromatography (HPLC). The Minimum Inhibitory Concentration (MIC) was determined by broth microdilution using spectrophotometer readings and the Minimal Fungicidal Concentration (MFC) was investigated. The reading data of the MIC was used to trace a cellular growth curve and calculate the Inhibitory Concentration for 50% of the cells (IC50) of the extract and fluconazole. The effect over the yeast morphology was verified using wet-chamber microculture and visualized through optical microscopy (40x). Results: HPLC detected the presence of flavonoids and phenolic acids. The extract presented fungistatic effect (MIC of 8.192 μg/mL). The IC50 of the extract and fluconazole varied between 4,008.7 to 5,116.8 μg/mL and 44.0 to 83.1 μg/mL, respectively. The extract inhibited the formation of hyphae at MICx2 against CA LM 77. For the CA INCQS 40006, the inhibition was verified at MIC/2. In the CT LM 23 and CT INCQS 40042 strains the presence of hyphae was considered absent at the MIC. Conclusion: The extract presented antifungal action on cell growth at elevated concentrations and an inhibitory effect of dimorphism in the tested Candida species.

Background: A series of novel substituted 2-mercaptoimidazoles was synthesised efficiently and in high yields using one-pot synthesis from m-hydroxyacetophenones. Methods: The structures of the newly synthesized compounds were established, their molecular activity was investigated against some bacteria and fungi were further validated using molecular docking study. Results: Reaction of o-hydroxyphenacylbromide (2) with substituted aniline and KSCN, in the presence of catalyst p-toluene sulfonic acid afforded 4(a-r) in good yield. The structure of compounds (4a-r) was confirmed by IR, NMR and MS. Conclusion: The compounds exhibited excellent antimicrobial potency against the tested microorganism.

Background: Hydrazones, one of the important classes of organic molecules, are pharmaceutical agents comprising –CO-NH-N=CH- group in the structure therefore and exhibiting significant biological activity. Methods: 5-Chloro-N’-[(substituted)methylidene] pyrazine-2-carbohydrazide (3a-g) and their Pd(II) complexes (4a-h) were synthesized and investigated in vitro anticancer activity on A549, Caco2 cancer and normal 3T3 fibroblast cell lines, using the MTT assay. Results: Anticancer activity screening results revealed that some compounds showed remarkable cytotoxic effect. Among them, 5-chloro-N'-[(4-hydroxyphenyl)methylidene] pyrazine-2-carbohydrazide (3c) displayed higher cytotoxic activity against A549 cancer cell line than the reference drug cisplatin. Conclusion: Compound 3c showed high cytotoxic activity against A549 cancer cell line but it showed low cytotoxic effect against normal 3T3 fibroblast cell line. Antiproliferative and antimetastatic effects of 3c were determined by the real-time monitoring of cell proliferative system (RTCA DP). The cell proliferation, metastatic and invasive activities of A549 cells were decreased due to increased concentration of 3c.

Background: Cancer continues to pose a great problem and burden on society despite new treatment options. While surgery, radiotherapy, and chemotherapy have led to major improvements in patient prognosis, newer treatments are needed to more effectively manage this disease in its advanced stage. Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK), which is catalytically active and under tight regulatory control. Dysregulation of its activity is strongly associated with tumorigenesis and cancer patients with altered EGFR activity tend to have a more aggressive disease, associated with a poor clinical prognosis. The family of EGFR has been intensively studied due to its strong influence on the formulation and deterioration of carcinoma. Thus, it is a good strategy that design anticancer agents by inhibiting the EGFR pathway. Methods: We group to obtain the six series compounds (8a-f, 9a-f, 10a-f, 11a-f, 12a-b and 13a-d). Hence we disclosed the design, synthesis and antitumor activity of novel quinazoline analogues against EGFR overexpression cancer cells A549 (human lung cancer), HepG-2 (human liver cancer), MCF-7 (human breast cancer) and PC-3 (human prostate cancer) and as well as the inhibitory on EGFR kinase. Moreover, apoptosis by acridine orange single staining and docking studies were presented in this paper as well. Results: Six series of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline (8a-f, 9a-f, 10a-f, 11a-f, 12a-b and 13a-d) were designed, synthesized and evaluated for the half maximal inhibitory concentration (IC50) values against four cancer cell lines (A549, HepG-2, MCF-7 and PC-3). Thirty target compounds showed moderate to excellent (1.49 - 50 μM) cytotoxicity activity against one or several cancer cell lines. The compound 13a showed the best activity against A549, HepG- 2, MCF-7 and PC-3 cancer cell lines, with the IC50 values of 1.49 ± 0.17 μM, 2.90 ± 0.24 μM, 1.85 ± 0.19 μM, 3.30 ± 0.22 μM, respectively. What’s more, the secondary amines were introduced to the target compounds to improve the water-soluble. The results showed that the compounds were beneficial to the cytotoxicity activity. Furthermore, the results prompted us that this series of compounds may be a kind of potential epidermal growth factor receptor (EGFR) kinase inhibitors. Conclusion: Six series of quinazoline derivatives bearing 2,3-dihydro-indole or 1,2,3,4- tetrahydroquinoline moiety (8a-f, 9a-f, 10a-f, 11a-f, 12a-b and 13a-d) were designed, synthesized and evaluated for the IC50 values of cytotoxicity against four cancer cell lines (A549, HepG-2, MCF-7 and PC-3). Thirty synthesized compounds showed moderate to excellent cytotoxicity activity against the different cancer cells. Especially, the compound 13a exerted antitumor effects in a dosage-dependent manner and the IC50 values of compound 13a were 1.49 μM, 2.90 μM, 1.85 μM and 3.30 μM against A549, HepG-2, MCF-7 and PC-3, respectively. From the antitumor activity data show that the compounds possessed selectivity for A549 and MCF-7 cancer cell lines. It meant that the compounds had better treatment effect on lung cancer and breast cancer. On the whole, the compounds substituted by 1,2,3,4-tetrahydroquinoline at C-4 position of quinazoline and (S)-tetrahydrofuran-3-ol at C-8 position of quinazoline were beneficial to the cytotoxicity activity. From the result of acridine orange (AO) single staining which indicated the compound 13a could induce apoptosis of A549 cells. From the result of Docking Studies, we hypothesized that the C-4 position of quinazoline were substituted by 2,3-dihydro-indole or 1,2,3,4-tetrahydroquinoline with the equal influence of the cytotoxicity activity. Overall, the results prompted us that this series of compounds may be a kind of potential EGFR kinase inhibitors.

Background: Cancer cells are described as an unregulated growth and spread of abnormal cells. Recently, cancer has become the most important major reason for deaths in the world. Methods: For anticancer activity, we have used the MTT method and determine the early/late apoptosis by flow cytometry. Results: The title compounds were procured by reacting 2-chloro-N-[4-(pyridin-4-yl)thiazol-2- yl]acetamide with some substituted piperazine derivatives. The in vitro anticancer activity of synthesized compounds was tested against C6 rat glioma cells and A549 human lung carcinoma cells. As a result, the compounds 3d, 3e, 3f and 3g have shown anticancer activity against both cell line. Conclusion: Specifically, compound 3f was determined as the most active compound against C6 rat glioma cells. Also, as understood, the core structure which is substituted with piperazine bridge, the heterocyclic aromatic derivatives are more active than phenyl or benzyl derivatives.

Background: Chemotherapy is a routine approach in treatment of patients with cancer, while side effects of chemotherapeutic drugs are inevitable. To minimize side effects, specific targeting of neoplastic cells is a promising strategy in cancer therapy. Sodium arsenite is a metalloid toxin with anti-neoplastic properties, but low selectivity and carcinogenic activity have limited its clinical usage. Methods: Targeting of HER2-overexpressing (SK-BR-3) and HER2-low expressing (MCF-7) cancerous breast cell lines by two different liposomal forms of sodium arsenite (bare liposome and trastuzumab-conjugated liposome) was investigated in the current study. Levels of HER2 expression in the above mentioned cell lines were confirmed by western blotting. Size and morphology of the constructed liposomes were characterized by atomic force microscopy (AFM) and dynamic light scattering (DLS). Viability of the cells after treatment was assessed using MTT assay. Results: Sodium arsenite in the free and liposomal forms showed growth inhibitory effects against both SK-BR-3 and MCF-7 cell lines in an examined concentration range of 1-20 μM, although this effect was more significant in SK-BR-3 cell line. Loading of sodium arsenite in anti-HER2 immunoliposomes significantly enhanced its cytotoxicity while the specificity was also improved. By encapsulation of sodium arsenite in anti-HER2 immunoliposomes, its efficacy in ablation of SKBR- 3 cells was increased about 1.4-fold compared to the free or liposomal forms. Conclusion: In conclusion, targeted delivery of sodium arsenite using anti-HER2 immunoliposomes can be considered as an alternative strategy for specific treatment of HER2-positive breast cancers.

Background: Nepeta species is a rich source of phytochemicals with multiple pharmacological activity. The aim of the present study was to study the cytotoxicity and pro-apoptotic activity of Nepeta binaloudensis different extracts and essential oil on prostate (PC3 and DU-145) and breast cancer (MCF-7) cell lines. Methods: To explore that cytotoxicity and apoptosis inducing activity, resazurin assay, propidium iodide (PI) staining of cells and western blotting analysis of PARP, Bax and Cyt c were performed. Results: Estrogen receptor (ER)-positive PC3, and MCF-7 cells were found to be more sensitive to N. binaloudensis in comparison with hormone-refractory DU-145 cells. Methylene chloride extract and the essential oil of N. binaloudensis showed the highest cytotoxicity (IC50 < 100 μg/mL). The amount of cytochrome C and Bax protein increased, and PARP was cleaved with methylene chloride fraction and essential oil of the plant which confirms induction of apoptosis. Conclusion: The present results suggested cytotoxic and apoptotic activity of N. binaloudensis on ER-positive breast cancer cells. Further phytochemical investigations are required to find phytochemical( s) with potential anti-tumor activity in this plant.

Background: B-Raf has become an important and exciting therapeutic cancer target. Methods: In the present work, molecular modeling protocols like molecular docking, MM/GBSA calculations, 3D-QSAR and binding site detection were performed on a dataset of 41 Type II inhibitors. Molecular docking was applied to explore the detailed binding process between the inhibitors and B-Raf kinase. Furthermore, the good linear relationships between G-Scores and MM/GBSA calculated and the experimental activity were shown. The satisfactory CoMFA and CoMSIA were constructed based on the conformations obtained by molecular docking. Results: The key structural requirements for increasing biological activity were verified by analyzing 3D contour maps of the 3D-QSAR models. FTMap and SiteMap were also used to detect the more efficient active binding site. Conclusion: New inhibitors were synthesized and the biological activities were evaluated, the results further validated our design strategy.

Background: Middle East Respiratory Syndrome coronavirus (MERS CoV) is a newly emerged viral disease with a fatal outcome. Methods: During the search for new antiviral drugs, MERS CoV papain-like protease (Plpro) was identified as a possible target. In this work, MERS CoV Plpro was investigated by virtual screening, enzyme inhibition and molecular dynamics to find new inhibitors. After the virtual screening of a dataset of small molecules, 5 compounds were selected for inhibitory studies. Results: Purine and imidazole-pyridine derivatives were identified as MERS CoV Plpro inhibitors with Ki values of 73 and 68 μM, respectively. The binding of inhibitors showed marked changes in both the fingers subdomain and Ubl domain, with negligible changes in the catalytic domain. The binding of inhibitors was associated with the formation of favorable hydrogen bonds with the side chains of Plpro S1648 or Y1760. Conclusion: Further optimization of the present set can lead to more potent inhibitors through the design of small molecules with improved binding affinity.

Background: The present paper focuses on the in vitro inhibition of some sedative drugs such as Midazolam, Propofol, Hipnodex, Ketamine, and Pental sodium on acetylcholinesterase (AChE), Butyrylcholinesterase (BChE), and α-glycosidase (α-Gly) enzymes. Methods: These drugs were tested in diverse concentrations, which showed positive effects in vitro AChE, BChE, and α-Gly activities. Ki values were 20.14, 94.93, 636.78, 416.42, and 953.75 μM for AChE, 17.52, 32.03, 88.02, 93.48, and 91.84 μM for BChE, and 10.87, 156.68, 48.21, 37.88, 151.01 μM for α-glycosidase, respectively. Results: An enhancing number of experiential observations show potentially harmful effects of sedative drugs on the extension of brain. Conclusion: Midazolam exhibited effective inhibitory activity compared with the other drugs for these enzymes.

Background: Inhibition of the DNA repair enzyme, tyrosyl-DNA phosphodiesterase 1 (TDP1), may increase the efficacy of cancer drugs that cause damage to tumor cell DNA. Among the known TDP1 inhibitors, there are compounds containing moieties of natural substances, e.g., monoterpenoids. In this work, we synthesized several compounds containing aromatic/ heteroaromatic amines and monoterpenoid groups and assessed their TDP1 inhibition potential. Methods: Structures of all the synthesized compounds were confirmed by 1H and 13C NMR as well as HRMS. The TDP1 inhibitory activity of the amines was determined by real-time fluorescence oligonucleotide biosensor. Results: The synthesized secondary amines had TDP1 inhibitory activity IC50 in the range of 0.79-9.2 μM. The highest activity was found for (–)-myrtenal derivatives containing p-bromoaniline or m-(trifluoromethyl)aniline residue. Conclusion: We synthesized 22 secondary amines; of these, 17 amines are novel chemical structures. Many of the amines inhibit TDP1 activity in the low micromolar range. Therefore, these compounds are promising for further study of their antiproliferative activity in conjunction with DNA damaging drugs.