Letters in Drug Design & Discovery - Volume 13, Issue 2, 2016

Plant growth regulators with the suitable concentrations had obvious effects on the accumulation of indole alkaloids in Catharanthusroseus cells#142;Four new compounds were synthesized as plant growth regulators and the accumulation effects of indole alkaloids in Catharanthusroseus cells were determined. Furthermore, some of them had the ability of promoting the accumulation of catharanthineandajmalicine in Catharanthusroseus cells. Compound 2 and 4 exhibited the best effects on the indole alkaloids production at 1μg mL-1; compound 2 displayed promoted the accumulation of catharanthineat 1μg mL-1, even at 10μg mL-1.

Synthesis, molecular docking study, and cytotoxic activity of a new group of 1,3,5-triaryl pyrazole derivatives were be studied. The antiproliferative activity of the final compounds were examined in MCF-7, AGS, HT-29 and NIH3T3 cell lines by MTT assay, using different concentrations of each compound to determine their IC50 . The cytotoxic activity of paclitaxel and doxorubicin were evaluated as positive controls. All compounds demonstrated cytotoxic activity in mentioned cell lines, in a dose dependent manner. Among all, compounds (5j, 5b, and 5d) showed the highest cytotoxicity in some cancerous cell lines with IC50 less than 5.0 μM. In addition, compound 5g, one of the most potent compounds, showed an interestingly low cytotoxic effect on NIH3T3 cell line, which is a noncancerous cell line. Together, our data suggest that the synthesized compounds have a partially selective mechanism of action against cancer cells and possibly a lower toxic effect on normal cells, making them interesting candidates for synthesis of their new derivatives. In molecular modeling, study all synthesized compounds were docked in the colchicine-binding site of tubulin α and β chains and the predicted binding energy was calculated. Our data indicate that these derivatives may present promising chemotherapeutic agents, possibly targeting microtubules.

The research on protein phosphorylation by kinases in various cellular processes is increasing significantly for the identification of kinase-based drugs. This is due to the fact that several kinasebased (anticancer) drug candidates have already been approved for clinical use and some are undergoing clinical trials as well. This scenario has amplified the momentum for the discovery of kinase-based drugs for other health problems such as hypertension, inflammation, and malaria. In this background, we reviewed here the research envisaged on the molecular modeling studies for inhibitors of Plasmodial protein kinases (PPKs) in the context of antimalarial drug design. This article focuses on modeling studies performed on the inhibitors of various malarial protein kinases such PfRIO-2 kinases (Plasmodium falciparum right open reading frame-2 protein kinase), thymidylate kinases (PfTMPK), cyclin-dependent protein kinases (Pfmrk), protein kinase-5 (PfPK-5), calcium dependent protein kinases (PfCDPK-1), glycogen synthase kinase-3 (PfGSK-3) and protein kinase-7 (PfPK-7). The presented information would be helpful for the researchers working on the identification of novel antimalarial kinase inhibitors in the context of widespread antimalarial resistance.

Objective: This study aimed to elucidate the antibacterial properties and therapeutic effect in refractory diabetic wound healing of a NanoAg-epidermal growth factor sustained-release carrier(NanoAg-EGF). Methods: as previous publishing, the sustained-release carrier of NanoAg-EGF can be conducted. The antibacterial properties and therapeutic effects of NanoAg-EGF were determined through in vitro bacterial growth inhibition experiments and in vivo wound healing experiments in diabetic rats. Results: In antibacterial experiments, NanoAg-EGF had strong properties of antibacterial which is similar to those of NanoAg (p>0.05). In diabetic wound healing experiments, NanoAg-EGF significantly shortened the wound healing time. Furthermore, at 3 days after wounding, the healing rate of each group was no different (p>0.05). However, at 7 and 13 days after wounding, with being higher than other four groups, the healing rates of sustained-release carrier treated diabetic rats were remarkable (p<0.05). Conclusion: NanoAg-EGF not only has good antibacterial properties, but can also promote rapid wound healing in diabetes.

A series of 4-phenylthieno[2,3-e][1,2,4]triazolo[4,3-a]pyrimidine-5(4H)-ones (5a–p) with triazole or other heterocyclic substituents (6–11) was synthesized and the compounds were evaluated for their anti-inflammatory activity using the xylene-induced ear-edema test. Pharmacological analyses showed that the compound 4-(4-chlorophenyl)thieno[2,3-e][1,2,4]triazolo[4,3-a]pyrimidine- 5(4H)-one (5m) exhibited the greatest anti-inflammatory activity (50.48% inhibition, 30 min after intraperitoneal administration) and was more potent than the reference drug, indomethacin. The peak activity of 5m was observed 4 h after oral administration, and it showed a higher anti-inflammatory activity than indomethacin did at a dose of 100 mg/kg.

A series of novel spiro-piperidinyl pyrazolones were synthesized starting from the commercially available ethyl nipecotate. The Boc protected ethyl nipecotate was reacted with 5-bromo-2-furaldehyde in the presence of LDA to afford the β -hydroxy ester which was converted to the β -keto ester by oxidation using manganese dioxide. Furthermore, β-keto ester was treated with hydrazine to form the spiro-piperidinyl pyrazolone scaffold. The phenyl/heteroaryl substituted (6ai) and hetero/arylethynyl substituted (7a-d) spiro pyrazolone were prepared by Suzuki and Sonogashira coupling followed by deprotection of the protecting group. All the synthesized compounds were evaluated for their invitro antiviral activity against BPXV on Vero cells. Compound 6c, 6d and 7c in the series showed potent antiviral activity.

The qualitative relationship between in vitro Caco-2 cellular transport and in vivo drug permeability allow using Caco-2 cell assay for intestinal absorption studies. In this work, atom-based bilinear indices and multiple linear regression (MLR) are applied to obtain models useful for the prediction of Caco-2 cell absorption. Making use of a previously reported database, we obtain four statistically significant MLR models, the best models shown R2=0.72 (s=0.435) for nonstochastic indices and R2=0.66 (s=0.464) for stochastic indices. No significant difference was found when comparing to previous reported studies. The models were internally validated using leave-one-out cross-validation, bootstrapping, as well as Y-scrambling experiments. Additionally, we performed an external validation using a test set, which yields significant values of R2 ext of 0.70 and 0.72 for stochastic models, showing a better predictive power. Furthermore, we define a domain of applicability for our models. These results suggest that our approach could offer an appropriate tool as an alternative to predict the absorption in Caco-2 cells in a short time and decrease experimental costs.

Natural products are recent emerging effective agents against many chronic human diseases. Curcumin (diferuloylmethane), the active constituent of turmeric (Curcuma longa), has gained much interest as a plant-based compound with pleiotropic biological activities. Curcumin has been shown to possess significant anti-oxidant, anti-carcinogenic, anti-inflammatory, and anti-microbial effects. Although the history of curcumin goes back thousands of years, the mechanism involved behind medicinal role of curcumin remains a topic of debate. In addition to this, its stability, solubility and bioavailability issues create reasons for further researches on this yellow molecule. Present article provides an overview of the history, chemistry, biological effects, and an update of mechanism(s) of action of curcumin.

A series of new N’-(arylidene)-2-[(1-(4-nitrophenyl)-1H-1,2,4-triazol-3-yl)oxy]acetohydrazide derivatives (1- 16) were prepared and tested for theira ntifungal activity against six plant pathogens, three human pathogens and two nonpathogen microorganisms. The target compounds were obtained with a multi-step reaction starting from 4- substitutedarylhydrazine derivatives and the structures of final compounds have been elucidated with IR, NMR, Mass spectroscopy data and elemental analysis results. The antifungal activity of the compounds was determined against eleven different Fusarium, Trichoderma, Aspergillus and Penicilliumspeciesby using microdilution method. Most of the target compounds showed excellent antifungal activity against a variety of fungal pathogens.

Tuberculosis remains a major health problem due to drug resistance and co-infection. Discovery of new drugs to counter tuberculosis is an urgent need. Multi-targeting strategy is one among the effective approach to combat the disease. Multi-targeting has minimal adverse effects. It is also difficult for Mycobacterium tuberculosis to survive and evolve into more drug-resistance strains in case of multi targeting. Lipases Rv0183 and Rv3802c were chosen as drug targets for the current study which are involved in the pathogen’s lipid and cell wall metabolism respectively. Seven potential dual inhibitors of tetrahydropyranyl and dibenzofuranone derivatives were discovered targeting respective substrate binding pocket of Rv0183 and Rv3802c. Molecule ZINC43860875 is the best hit with predicted free energy of binding (ΔG) of -10.80 and -10.97 kcal/mol against Rv0183 and Rv3802c respectively. Based on contact footprinting studies, several molecules were designed with better ΔG through modification of functional groups that favor van der Waals and ionic interactions. Molecule Rv0183-1 (combination of potential inhibitors ZINC43860875, ZINC28262919 and ZINC11616855) was identified as potential dual inhibitor against Rv0183 and Rv3802c with ΔG of - 18.08 and -16.14 kcal/mol respectively. The current study paves way towards design and development of new multi-target inhibitors to combat tuberculosis.