Letters in Drug Design & Discovery - Volume 11, Issue 7, 2014

The anticancer drug candidate 1,3-di(p-methoxybenzyl)-4,5-di(p-isopropylphenyl)-imidazol-2-ylidene copper( I) bromide (WBC4) was tested on the NCI 60 cancer cell panel in vitro. WBC4 showed very good activity against a wide range of human cancer cell lines inclusive renal cell cancer with an average GI50 value of 288 nM. This encouraged maximum tolerable dose (MTD) experiments in mice, where a MTD value of 10 mg/kg was determined with single injections to groups of 2 mice. In the following tumor xenograft experiment WBC4 was given at 5 and 10 mg/kg in 5 injections to two cohorts of 6 CAKI-1 tumor-bearing NMRI:nu/nu mice, while a control cohort of 6 mice was treated with solvent only. At the higher dose of 10 mg/kg WBC4 showed borderline toxicity leading to 2 mortalities, while a significant T/C value of 0.38 was observed on day 32. At the lower dose of 5 mg/kg WBC4 induced mild and reversible body weight loss with no toxic deaths. At this dose WBC4 showed an identical significant T/C value of 0.38 on day 32, when compared to the treatment group. Immunohistochemistry for the proliferation marker Ki-67 did not show significant changes due to WBC4 treatment in the animals. However, anti-angiogenic effects by WBC4 treatment were observed in CD31 immunohistochemistry. Here, significant reduction in microvessel number, area and ratio was determined in tumors treated with 10 mg/kg of WBC4.

New pyrazole-based thiazolyl hydrazone derivatives were obtained via the ring closure reaction of 3,5- dimethyl-1H-1-phenylpyrazole-4-carboxaldehyde thiosemicarbazone with 2-bromoacetophenone derivatives. The compounds were investigated for their cytotoxic effects on A549 and NIH3T3 cell lines. Among these compounds, compound 2i bearing a trifluoromethyl substituent can be identified as the most promising anticancer agent against A549 cancer cell lines. Compound 2i exhibited its inhibitory effect on A549 cells with an IC50 value of 0.0316 mM, whereas cisplatin showed its anticancer activity with an IC50 value of 0.01 mM. According to the IC50 values, the inhibitory effect of compound 2i on A549 cells can be considered to be selective when compared with its effect on NIH3T3 cells.

This study describes the synthesis of four 2,4,5-triarylimidazole derivatives and their anticancer activities. The target compounds were prepared from the reaction of benzaldehyde and benzoin derivatives in presence of ammonium acetate and ammonium vanadate. All the synthesized compounds were screened for anticancer activities against T47D and MDA-MB231 cell lines using the MTT assay. However, our obtained results indicated a significant difference between colchicines cytotoxicity and their homologs on treated MDA-MB231 and T47D cells; one compound (4a) showed a significant IC50 on MDA-MB231 cells in cell culture assay.

The structure of the compound depends on connectivity of its constituent atoms. Topological descriptors based on connectivity can reveal the role of structural and substructural information of molecules in estimating biological activity. The present study involves conceptualization of six detour cum distance matrix based topological descriptors (TDs) termed as relative distance sum descriptors and relative distance product descriptors (denoted by S 1 R , S 2 R , S 3 R , S 4 R , S 1 RP and S 2 RP ) as well as their topochemical versions (denoted by S 1 R c , S 2 R c , S 3 R c , S 4 R c , S 1 RP c and S 2 RP c ). The proposed descriptors have been specifically designed to take care of the molecules containing cyclic substituents. An inhouse computer program was utilized to compute the values of the proposed TDs for all possible four, five and six membered hydrogen depleted structures. Proposed TDs were assessed for similarity analysis, intercorrelation, degeneracy, discriminating power, and sensitivity towards branching apart from relative position of substituent in molecules containing cyclic moieties. The said TDs exhibited negligible degeneracy, high sensitivity towards branching/relative position of substituent(s) in cyclic structures amalgamated with exceptionally high discriminating power. The above mentioned attributes provide proposed descriptors a huge potential for use in characterization of molecules, lead identification/ optimization, combinatorial library prototype, dissimilarity/similarity studies and (Q)SAR/QSPR/QSTR/QSPkR studies so as to facilitate drug design. This has been further supported by application of the proposed descriptors on the real dataset in the part-II of the manuscript.

β-secretase (BACE1) inhibition has emerged as a most promising target for the treatment of Alzheimer’s disease. In the present study an in silico approach has been successfully utilized for the development of diverse classification models for the prediction of BACE1 inhibitory activity using a dataset consisting of 42 differently substituted aminohydantoin analogues. Classification tree (CT), moving average analysis (MAA) and random forest (RF) were utilized for development of models. Two out of three MDs identified by CT as the most important were the detour cum distance matrix based topological descriptors proposed in part-I of the manuscript. Various models resulted in the prediction of BACE1 inhibitory activity with an overall accuracy of >92%. Overall accuracy, non-error rate, intercorrelation analysis, specificity, sensitivity and Mathew’s correlation coefficient (MCC) were utilized to determine statistical significance of the said models. Proposed models provide an immense potential for furnishing lead molecules so as to unfold potent BACE1 inhibitors for the treatment of Alzheimer’s disease.

A series of novel carvacrol and thymol derivatives containing 5-phenyl-2-furan were synthesized. The antitumor tests showed that the title compounds exhibited promising activity against Bel-7402 and KB. The fungicidal tests showed that most of the title compounds had a considerable effect on the selected fungi. Generally the bioactivity of the carvacrol and its derivatives were better than that of the thymol and its derivatives. The substituted groups on the orthoand para- positions gave better activity than that of ones on the meta-position.

Dipeptidyl peptidase-IV (DPP-IV) is well known to be an attractive therapeutic target to treat type II diabetes. The aim of this work is to determine the residues which make great contributions to inhibitor binding by comparing the interactions between different inhibitors and residues in DPP-IV. To achieve this, two DPP-IV/inhibitor complexes were studied by molecular dynamics simulations. Hydrogen bond and interaction energy analysis were then carried out. The results indicate that several residues could make great contributions to inhibitor binding. Medicinal chemists may have priority to choose these residues to form strong non-bonded interactions with designed compounds. It is hoped that this work could help medicinal chemists to design more potent DPP-IV inhibitors.

MEK proteins play a critical role in tumor proliferation, differentiation, and survival. Hence MEK1 inhibitors are of particular importance in the treatment of related diseases. The present study describes pharmacophore-based 3DQSAR model generation based on 82 known inhibitors of MEK1 allosteric binding cavity. The best pharmacophore model developed consisted of four features, namely AHHR. The model was used as a query to screen the databases of almost 1.3 million compounds. Finally, 8 hits were indentified and the docking study manifested that these compounds interacted with MEK1 well. Finally, 10 ns MD simulations of the obtained ligand-receptor system were performed. The stable binding mode of the system was determined. Our results showed that the identified 8 hits would be useful for the development of potent MEK1 agents.

Inherited defect of the gene ATP7B causes malexcretion of copper in the bile and leads to several complications that need treatment to deplete it from organs. Current therapy of Wilson disease, D-penicillamine has very serious side effects and drug with optimum therapeutic effects and minimum side effects is of importance. In the present study ciprofloxacin was conjugated with an anionic globular dendrimer to lower the intracellular copper concentration. The results showed its efficacy and safety to certain levels. Based on the results, ciprofloxacin-anionic linear globular dendrimer conjugate can be a useful option to reduce intracellular copper concentration and an investigational therapeutic agent in Wilson disease.

Herein, we have investigated novel pyrimidine nucleosides bearing a 4’-carboxyl functionality (6-10, 13 and 15) as anti-HCV agents. In this new class of compounds, 7, 9, 10 and 15 demonstrated in vitro anti-HCV activity similar to or better than a known anti-HCV drug, ribavirin. In this work, we also, surprisingly, identified a 3’-sulfoxide analog of 3’-thiacytidine (16), obtained as a side product during the synthesis of 15, as a potent inhibitor of HCV replication at the concentration similar to that of ribavirin. No detectable in vitro cytotoxicity was observed for the investigated compounds up to the highest concentration tested.

Meloxicam is a non-steroidal anti-inflammatory drug used in the treatment of rheumatoid arthritis, osteoarthritis and other inflammatory diseases. However, its prolonged use is associated to several side effects like gastrointestinal perforations, ulcerations and bleeding, probably due its low aqueous solubility and wettability after oral administration. These side effects can reduce patient compliance and discourage physician from prescribing this drug. In this way, inclusion complexes between meloxicam and methyl-β-cyclodextrin were prepared in aqueous solution by phase solubility studies and in solid state by freeze-drying method in order to increase drug solubility. The physicochemical characterization of the prepared complexes in solid state was performed by different techniques. Furthermore, hydrogels containing poloxamers were prepared for topical administration of meloxicam. For this purpose, solid inclusion complexes were incorporated in hydrogels with different poloxamers composition. The rheological behaviour of these formulations was studied by different methods and the drug release from optimised hydrogels was evaluated by Franz diffusion cells, applying some mathematical models to analyse the drug release mechanism from hydrogels. Results from phase solubility studies showed the formation of inclusion complexes between meloxicam and methyl-beta-cyclodextrin in aqueous solution in a 1:1 stoichiometry and an increase in drug solubility. Different techniques employed indicated complete formation of complexes in solid state prepared by the freeze-drying method. Moreover, the performed set of rheological studies, easily adapted to similar systems, demonstrated that hydrogels containing poloxamers and cyclodextrin may provide a suitable supramolecular platform for meloxicam delivery as a novel strategy to increase drug bioavailability.

In the present article, the antimicrobial properties of ethyl 4-amino-2-mercapto-6-arylpyrimidine-5-carboxylate (2a-h) and ethyl 2-(2,4-dinitrophenylthio)-4-amino-6-arylpyrimidine-5-carboxylate (3a-h) were studied. Biginelli typed three component reaction between an aldehyde, ethyl cyanoacetate and a thiourea constituent which gives a rapid facile 3,4-dihydropyrimidine ring (1a-h), which on aromatization using SeO2 and followed by reaction with 1-chloro-2,4- dinitrobenzene giving final product (3a-h). The structures of all synthesized compounds have been established by extensive IR, NMR and Mass studies and were assayed for their antibacterial activity against S. aureus MTCC-96 and E. coli MTCC-443 and antifungal activity against A. niger MTCC-282 and C. albicans MTCC-227 at different concentrations compared with Ampicillin, Chloramphenicol, Ciprofloxacin and Griseofulvin as standard drugs. The activity was measured in the zone of inhibition. Among the all synthesized compounds, 2a, 2d, 3a, 3d and 3g are significantly active against bacterial strain, while other compounds are weakly active. All the compounds are moderate to low active against fungal strain.

The high toxicity and the growing resistance are the major drawbacks of available antileishmanials. Our previous in vitro studies have identified oxabicyclo[3.3.1]nonanones as antileishmanial agents that act on the redox enzymes of the parasite. In the current study, antileishmanial activity of 4-(4,4,8-trimethyl-7-oxo-3-oxabicyclo[3.3.1]non-2-yl)- benzoic acid methyl ester (PS 203) the most potent oxabicyclo[3.3.1]nonanone identified in our previous study is evaluated using the hamster model. There was 77.29 ± 3.0 % inhibition of parasite growth observed after a 5-day treatment of 5 mg/kg body weight dose. Further, the in vivo toxicity study of the compound in Swiss albino mice revealed no hepatic or renal toxicity.

A series of 4-methyl-N-(5-substituted-1, 3,4-thiadiazol-2-yl)-1,2,3-thiadiazole-5-carboxamide 6a~6j. The chemical structures were confirmed by 1H NMR, FTIR, MS, and elemental analysis. All the compounds were investigated for antifungal activity. The antifungal activity results indicated that compound 6a exhibited good activities against C. arachidicola. It can be compared with the commercial drug. The compounds 6e, 6f, 6i, 6j exhibited moderate activity.

The ABHD6 and ABHD12 are newly discovered post-genomic proteins which act as 2-arachidonoylglycerol hydrolases. Their physiological importance is largely unknown, however high expression of ABHD6 is attributed to some forms of cancer. Only a few inhibitors are known for ABHD6 and ABHD12 enzymes. In search for novel inhibitors of ABHD6 and ABHD12 hydrolases we tested a set of heterocyclic compounds which are lipophilic as required by the protein binding pockets and possess suitable properties for being tested in the designed assay. The rationale of the study may be summarized as follows: (1) almost all the compounds are relatively lipophilic; (2) some of the selected compounds exhibited anticancer activity; (3) some of the selected compounds shared the same structural features with known ABHD6 inhibitors and (4) physicochemical properties of the compounds make it possible to test them in the in vitro assay against ABHD6 and ABHD12 hydrolases. Although the studies did not make it possible to identify novel very potentABHD6 and ABHD12 inhibitors, we have identified 6 weak inhibitors of ABHD6 and ABHD12 (non-selective) and inhibiting both enzymes. The results obtained may be helpful for the design of novel active compounds.