Letters in Drug Design & Discovery - Volume 14, Issue 3, 2017

Background: Glucokinase activators (GKAs) represent a promising opportunity for the treatment of type 2 diabetes due to the fact that glucokinase (GK) is a key regulator of glucose homeostasis. Method: Based on structure-based design strategies, a series of novel orotic acid amide derivatives have been synthesized. Lead optimization led to the discovery of several active compounds via in vitro enzyme assays. Compared to the positive control compound GKA22, compounds 10j, 11h and 11i exhibited identical or even higher activity. Furthermore, docking simulation of compound 11i further demonstrated that the hydrogen atom of amide and the nitrogen atom of pyrimidine both bound to Arg63 via hydrogen bonds. Results: Hydrogen bond interactions were also observed between the two oxygen atoms of 2-methoxy-1- methyl-ethoxy moiety and Thr65. Both ends of the molecule were fixed in allosteric pocket of glucokinase, which was in favour of keeping active conformation.

Introduction: After using insecticides over many years, the resistance and environmental issues have become great challenges to crop protection. Modern agriculture calls for new insecticidal candidates. Phthalic diamide insecticide containing adjacent two amide group were favored for its new mode of action. Most chemical optimizations of phthalic diamide insecticide focused on amide groups. Modifications on phenyl part including fewer substituent types. Objective: The objective of this article was to investigate the insecticidal activities variation by alter the orientation and distance of two amide by replace the phenyl part with oxydibenzene and diphenyl-amine. Results: The target compounds were synthesized by using Cu/CuI catalyzed Ullmann coupling and sulfonyl-O-acryl mixed-anhydride as reactive intermediate. All target compounds were evaluated against armyworm (Mythimna sepatara). Two of synthetic compounds containing multifluoro-alkoxyl substituent showed mortality rate of 100% at 500 mg L-1. DFT-based Potential energy surface scanning showed that the relative energies of three conformations of insecticidal compounds were very similar. Conclusion: We designed, synthesized and characterized seventeen novel compounds for the insecticidal candidates. Two of them were found to be insecticidal. A preliminary structure-activity relationship showed that the multifluoro-alkoxyl groups on the benzene were preferred. The compound d5 could be a lead compound for further research.

Background: ALK was a receptor tyrosine kinase (RTK) belonging to the insulin receptor superfamily. Many ALK fusion partner genes have been identified in NSCLC, such as NPM, EML4, TFG, KLC1, KIF5B and PTPN3. There had been many reports of potent ALK inhibitors discovered by innovative pharmaceutical companies. Methods: A series of 2,4-diarylaminopyrimidine-containing ALK inhibitors were synthesized by Kim as the data set for the 3D-QSAR studies are described in this paper. CoMFA and CoMSIA models were performed using Sybyl X 2.0 package. Molecular docking analysis was carried out using Surflex-Dock in the SYBYL-X 2.0 package. Results: Firstly, The detailed contour analysis of ligand-based CoMFA and CoMSIA models enabled us to identify several structural requirements as mentioned in above paragraph for the observed inhibitory activities: 1) R1: bulk substituents, electronegative substitutes at para-site of R1 aromatic ring, electropositive substitutes at 2-site and 5-site of R1 aromatic ring, hydrophobic, and hydrogen bond acceptor (favorable); 2) R2: small substitutes, hydrophobic and H-bond donor (favorable); electrostatic field had little effect on biological activity; 3) R3: medium sized substitutes and electronegative substituents at orth-site of R3 aromatic group, H-bond donor at 2-site and 3-site of R3 aromatic group, and hydrogen bond acceptor at the para-site of R3 aromatic group (favorable); small substitutes and electrostatic field at para-site of R3 ring, and hydrophobic had little effect on biological activity. Scondly, the conformations obtained after MD is more stable than the docked conformations. MD simulation is performed in a more realistic environment, and much closer to physiological conditions. Conclusion: The contour maps obtained from the CoMFA, CoMSIA analysis provided useful information about the intermolecular interactions of the inhibitors with the surrounding environment. In addition, the 3D-QSAR models, molecular docking and MD simulations exhibit a good consistency indicating that the derived models are reliable and robus. The results from the 3D-QSAR models, molecular docking, and MD simulations should lead to a better understanding of the structural features needed to create novel potential ALK inhibitors.

Background: Metabolic syndrome (MetS) has been recognized as a leading cause of various health complications, affecting many organs including the kidneys. The aim of the current study was to investigate the effect of pentoxifylline (PTX) on the renal dysfunction which is associated with MetS. Methods: MetS was induced in male Wistar rats by adding 10% fructose to their drinking water, as well as placing the animals on a high fat salt diet for 12 weeks. Pentoxifylline was then administered (30 mg.kg-1.day-1) orally starting from the 9th week for a duration of 4 weeks. Results: Despite having no significant effect the developed hyperinsulinemia associated with MetS, pentoxyfylline administration in the last four weeks alleviated the proteinuria associated with fructose, fat and salt (12 weeks)-induced MetS in rats. In order to investigate the mechanism of action of pentoxifylline, its effects on inflammatory mediators and enzymes was explored. Pentoxifylline significantly decreased urine 8-isoprostane levels as well as the kidney inducible nitric oxide synthase (iNOS) levels in MetS animals. An investigation of kidney glutathione reductase enzyme revealed a significantly decreased activity in MetS animals treated with pentoxifylline compared with untreated MetS rats. Pentoxifylline had no effect on the elevated kidney glutathione peroxidase found in MetS group. Conclusion: The short-term administration of pentoxifylline in rats with MetS, was found to ameliorate proteinuria and the low grade inflammation which are associated with MetS.

Background: Tuberculosis is the leading cause of death, especially among the developing countries. Emerging cases of bacilli drug resistance and its co-infection with HIV have led to an increasing occurrence of treatment failure, which drive the need of new and safe drug, having potent anti-TB activity including the drug resistant strains. Method: In the present study, fifteen novel tetrahydroquinoline based propanehydrazides were designed, synthesized, characterized using spectral techniques (FTIR, 1H NMR, Mass and elemental analysis) and in-vitro evaluated against M. tuberculosis (H37Ra strain). Synthesized compounds were also evaluated for cytotoxicity against human lung fibroblast cells. Conclusion: The result of the anti-tubercular studies revealed that, two compounds 7g and 7o exhibited significant antitubercular activity with MIC values below 20 μg/mL, with safety index greater than 9.94 and 10.57, respectively. Moreover, none of the compounds showed toxicity against lung fibroblast cells at tested concentration of 512 μM. SAR studies of tested compounds revealed that, antitubercular potency of compounds changed significantly with nature and position of the substituent.

Background: A 3D-QSAR model of KATP channel activation by benzopyran derivatives has been developed using molecular field alignment method. The model based on pED50 values required for myorelaxant activity by 4, 6 disubstituted benzopyrans has been explored. Discussion: The results are critically discussed based on molecular field of the structures and their alignment with the most potent compound of the series, i.e. Cromakalim. The model had an R2 of 0.99 and the training set of 25 compounds. A Leave-Many-Out (LMO) cross-validated value (Q2) of 0.496 with RMSETraining of 0.020 indicated that the model had optimum predictive ability on structurally diverse 4, 6 di-substituted benzopyrans. Conclusion: The developed model and the participating molecular field suggest the potential of replacement groups of 4, 6 di-substituted benzopyrans for structural optimization for the enhancement of biological activity.

Background: Biotransformed bufadienolides are new kind of cytotoxic products with novel structures. Method: Herein, 3D-QSAR analyses were performed on bufadienolides using CoMFA and CoMSIA to learn the structure-activity relationship and the mechanism of action of these compounds. The cross-validated q2value of CoMFA is 0.648 and q2value of CoMSIA is 0.635. The non-crossvalidated r2 value of CoMFA is 0.963 and r2 values of CoMSIA is 0.961. The 3D-QSAR models we obtained were illustrated through CoMFA and CoMSIA contour plots. Results: That will be valuable in predicting cytotoxic activities against cancer cells, and could be used to design potent anticancer drugs.

Background: 21 novel 1-alkoxy-1H-benzo[d]-1,2,3-triazole compounds were designed, prepared and evaluated for their antidepressant and anticonvulsant effects in mice. Method: Compound 19 significantly decreased immobility time in the FST without altering the locomotor activity in the open field test, and exhibited higher levels of efficacy than the reference standard fluoxetine. Compound 19 significantly increased 5-HT, NE and 5-HIAA levels in mice brain, implying that the antidepressant activity might be mediated by these neurotransmitters. In the seizure test, compound 19 also showed better anticonvulsant activity against MES, whereas had not shown neurotoxicity (300 mg/kg). Conclusion: Our data indicated that compound 19 could potentially be used as the antidepressant drug in patients with epilepsy.

Background: A series of novel 2,6-dichloro-4-(trifluoromethyl)phenyl)-3-(trifluoromethyl) - 1H-pyrazole-4-carboxamide derivatives were designed and synthesized. Method: All the title compounds were confirmed by 1H NMR and MS. Results: The primarily nematicidal activity results indicated that some of them exhibited moderate control efficacy against the tomato root-knot nematode disease caused by Meloidogyne incognita.

Background: Decreased efficiency of artemisinin combination therapy (ACT) and the declining efficacy of affordable drugs for malaria is a major concern with half of the world population living in countries endemic to the disease; hence the development of the next generation anti-malarial drugs is the need of the hour. Objective: The present study is the first attempt to characterize the three dimensional structure of Plasmodium falciparum X-prolyl aminopeptidase (PfAPP), a newly detected target for malaria treatment. Method: The three dimensional structure of the protein had been modelled and validated using different tools. Also, the stability of the model was analyzed by molecular dynamics simulation (MDS) studies. The MDS studies involving trajectory based analysis of root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of the system revealed stability of the system throughout the dynamics, the model was used for prediction of ligand-binding site of the protein. Results: Comparative sequence and structural analysis of the model with the template (human homologue APP1) revealed the conservation of two of the five active site residues and functionally important secondary shell residues surrounding the active site, suggesting the possibility of conserved catalytic mechanism in the malarial X-prolyl aminopeptidase. In the absence of the experimental crystal structure of PfAPP, the proposed model could serve as a basis for ligand docking prediction and elucidation of its catalytic mechanism that might be useful for the development of new inhibitors accounting for the rational structure-based drug design of the efficient next generation anti-malarial therapeutics.

Background: Escherichia coli has an adaptive metabolism and many strains are resistant to classical antibacterial agents, and due to this resistance, it can cause severe clinical infections. In addition, few novel antibacterial agents have been developed in recent years, which corroborate with antimicrobial resistance. For this reason, innovative antimicrobials with novel targets and modes of action are needed. Objective: The aim of this study was to determine the antibacterial and anti-biofilm activity of metals (mercury, copper, silver, and cadmium) coordinated with sulfamethoxazole (SMZ) against Escherichia coli (ATCC® 35218TM). Methods: We used the minimum inhibitory concentration (MIC) technique to evaluate the compound antibacterial properties. Additionally, we verified metal-coordinated SMZ efficacy against bacterial motility, slime production and biofilm formation. We also quantified the bacterial respiratory activity in the presence of those compounds. Results: We showed that metal-coordinated SMZ displayed E. coli antibacterial activities in concentrations are lower than the ones found to SMZ. Besides, metal-coordinated SMZ were able to inhibit biofilm formation and also decrease E. coli motility in lower concentrations than found in a classical antibiotic. All tested compounds stimulated the bacteria respiratory chain, which can be related to the mechanism of their antibacterial activity. Conclusion: Our results suggest that metal-coordinated SMZ enhanced the antibacterial and anti-biofilm activity against E. coli when compared with SMZ free.

Backkground: Primaquine thiazolidinone derivatives are proposed as promising antimalarial candidates to be tested as primaquine substitutes. Method: Molecular docking and dynamics simulations were applied in the analogues-NQO2 complexes to understand their interactions, and the toxic potential of these derivatives in a set of 16 target proteins was also studied. Results: The results of our study suggest that the interactions of five thiazolidinone primaquine derivatives with NQO2 are stronger than the interaction of primaquine and NQO2. The analogue 5nprotein complex seems to be the most stable compared with the primaquine-protein complex. The analogues 5n and 5o are predicted to be in the same class of toxic potential as primaquine. Conclusion: Their interactions with the cytochrome P450 enzymes are also predicted to be weaker, indicating that a better activity/toxicity balance compared with primaquine may be reached.

In antiretroviral therapy Integrase Inhibitors (INIs) have become a key component since the approval of raltegravir in 2007 followed by the recent approval of elvitegravir in 2012. The next generation compound dolutegravir has obtained the approval from USFDA in August 2013. Dolutegravir possesses distinct characteristics like prolonged half-life, once-daily dosing without the need for any booster along with no significant effect of food on its pharmacokinetics. Earlier reports have shown that H51Y and R263K define a unique resistance pathway for dolutegravir. Dolutegravir is effective in both initial therapy and in the salvage of many patients who display resistance to both raltegravir and elvitegravir. Furthermore, due to its favorable metabolic profile and, without any dose adjustment, it can be co-administered with most of the other approved antiretroviral agents. These characteristics of dolutegravir along with reports from various ongoing phase III trials showed that it can be a promising investigational drug for future clinical uses. This review focuses on recent data of dolutegravir from well-designed clinical trials, resistance, with comparative drug interaction of various INIs.