Medicinal Chemistry - Volume 11, Issue 5, 2015

Nitrogen-containing bisphosphonates (N-BPs) are important drugs widely used in a variety of bone resorption diseases. These compounds target the farnesyl pyrophosphate synthase (FPPS), a key enzyme of the mevalonate pathway involved in several pathologies. The inhibition of FPPS is a promising pharmacological approach and the development of structure-based methods for the prediction of the enzyme-inhibitor binding energy, can provide a guide for the rational design of new N-BPs. In this study multiple docking and post-docking strategies were applied to develop an effective computational workflow able to correctly predict the binding geometry and energy of a diverse set of known N-BPs. Preliminarily, we identified a model structure of the target allowing to predict the binding pose for all studied ligands and improving the estimation of the target-ligand interaction energies. A significant correlation between calculated and experimental binding affinities was found by dividing the whole group of N-BPs inhibitors into two subsets according to the structure's size, suggesting that the contributions to the binding energy are differently weighted in the two groups and that the FPPS inhibition mechanism may be based on ligand dimensions. The ob tained quantitative models can be further exploited for either screening or optimization studies of newly designed N-BPs.

In this work, three different groups of drugs such as 12 analgesic drugs, 11 cardiovascular system drugs and 36 “other” compounds, respectively, were analyzed with cluster analysis (CA), principal component analysis (PCA) and factor analysis (FA) methods. All chemometric analysis were based on the chromatographic parameters (logk and logkw) determined by means of high-performance liquid chromatography (HPLC) and also by molecular modeling descriptors calculated using various computer programs (HyperChem, Dragon, and the VCCLAB). The clustering of compounds were obtained by CA (using various algorithm as e.g. Ward method or unweighted pair-group method using arithmetic averages as well as Euclidean or Manhattan distance), and allowed to build dendrograms linked drugs with similar physicochemical and pharmacological properties were discussed. Moreover, the analysis performed for analyzed groups of compounds with the use of FA or PCA methods indicated that almost all information reached in input chromatographic parameters as well as in molecular modeling descriptors can be explained by first two factors. Additionally, all analyzed drugs were clustered according to their chemical structure and pharmacological activity. Summarized, the performed classification analysis of studied drugs was focused on similarities and differences in methods being used for chemometric analysis as well as focused abilities to drugs classification (clustering) according to their molecular structures and pharmacological activity performed on the basis of chromatographic experimental and molecular modeling data. Thus, the most important application of statistically important molecular descriptors taken from QSRR models to classification analysis allow detailed biological (pharmacological) classification of analyzed drugs.

A new series of (E)-N,2,3-triarylacrylamide derivatives were designed and synthesized as potent anticancer agents. Cytotoxicity of the 26 target compounds was evaluated in vitro against six cancer cell lines (HCT116, A549, MDA-MB-468, HepG2, SKNMC and SK-OV-3) by Sulforhodamine B colorimetric assay. The most promising compound, 4h, was as potent as the reference drug cisplatin (DDP). Preliminary structure–activity relationship (SAR) data provided guidance for further design and discovery of (E)- N,2,3-triarylacrylamide scaffold anticancer agents.

2,4-Disubstituted thiophene derivatives were synthesized and assessed for antiinflammatory and anti-cancer activities by targeting two important enzymes of the arachidonic acid metabolism. Both lipoxygenase and cyclooxygenase enzymes play vital role in chronic inflammation and carcinogenesis. Previous studies have proved that COX-2 and 5-LOX are highly activated in various types of cancers; hence inhibition of these clinically important enzymes constitutes the essential criterion for the suppression of tumor progression and metastasis. Among the tested derivatives, 2d and 2g compounds emerged as potent inhibitors of lipoxygenase and cyclooxygenase enzymes. The potent inhibitor of cyclooxygenase was further tested for in vitro cytotoxicity on cervical cancer (HeLa) cells and in vivo tumor model studies using EAT bearing mice where 2-(3,4,5- trimethoxyphenyl)-4-(N-methylindol-3-yl) thiophene (2g) showed eloquent activity. Further, in silico modeling results confirmed the active catalytic ligand binding pockets, which is evident from higher atomic contact energy values of 2d and 2g than compared to standard drug. Thus, 2g may find better application in management of inflammation and in proapoptotic therapeutic engineering.

Azolium (imidazolium and benzimidazolium) salts are known as stable precursors for the synthesis of Metal-N-Heterocyclic Carbene (M-NHC) complexes. Recently, some reports have been compiled indicating that benzimidazolium salts have anticarcinogenic properties. The current research is the further investigation of this phenomenon. Three ortho-xylene linked bis-benzimidazolium salts (1-3) with octyl, nonyl and decyl terminal chain lengths have been synthesized. Each of the compounds was characterized using FT-IR and NMR spectroscopic techniques. The molecular geometries of two of the salts (1-2) have been established using X-ray crystallographic technique. The compounds were tested for their cytotoxic properties against three cancerous cell lines namely, human colon cancer (HCT 116), human colorectal adenocarcinoma (HT- 29) and human breast adenocarcinoma (MCF-7). Mouse embryonic fibroblast (3T3-L1) was used as the model cell line of normal cells. The compounds showed selective anti-proliferative activities against the colorectal carcinoma cells. For HCT 116 and HT-29 cells, the IC50 values ranged 0.9-2.6 μM and 4.0-10.0 μM, respectively. The salts 1 and 3 displayed moderate cytotoxicity against the breast cancer (MCF-7) cells with IC50 58.2 and 13.3 μM, respectively. However, the salt 2 produced strong cytotoxicity against MCF-7 cells with IC50 4.4 μM. Interestingly, the compounds demonstrated poor cytotoxic effects towards the normal cells (3T3-L1) as the IC50 was found to be as high as 48.0 μM. Salts 2 and 3 demonstrated more pronounced anti-proliferative effect than the standard drugs used (5-Flourouracil and Tamoxifen).

A series of 17-phenylpropylamine/phenoxyethylamine-substituted derivatives of geldanamycin (GA) was synthesized and evaluated for the anti-proliferation activity on human cancer cell line MDA-MB-231. All the derivatives exhibited potent cytotoxicity with IC50 values range from 0.35 to 1.03 μM. Among them, 17-(2-phenoxyethylamino)-17-demethoxygeldanamycin (3) was identified as the most potent compound. Hepatotoxicity test in mice demonstrated that the levels of both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) of 3-treated group were lower than that of GA-treated group, indicating that compound 3 was a promising antitumor candidate. Additionally, the Hsp90 inhibitory activity of compound 3 was more active than 17-AAG. Docking and molecular dynamics (MD) refinements of this new series of GA derivatives were also investigated, suggesting a theoretical model between 17- phenylpropylamine/phenoxyethyl-amines and Hsp90.

Alzheimer’s disease (AD) is a type of neurodegenerative disorder which is responsible for many cognitive dysfunctions. According to the most accepted cholinergic hypothesis, cholinesterases have a major role in AD symptoms. The use of small molecules as inhibitors is one of the most useful strategies to control AD. In the present work, a series of N-phenylthiazol-2-amine derivatives was screened against acetylcholinesterase (AChE) from Electrophorus electricus and butyrylcholinesterase (BChE) from horse serum by using Ellman’s method, using neostigmine and donepezil as reference drugs. Some of the assayed compounds proved to be potent inhibitors for AChE and BChE activity. N-(2,3-dimethylphenyl)thiazol-2-amine, 3j was found to be the most active inhibitor among the series with IC50 value of 0.009 ± 0.002 μM and 0.646 ± 0.012 μM against AChE and BChE, respectively. Molecular docking studies were carried out in order to better understand the ligand binding site interactions.

A series of piperidyl-thienyl & 2-pyrazoline derivatives of quinolyl-thienyl chalcones were tested to observe the structural characteristics for the monoamine oxidase inhibitory (MAO) activity. In both these series, a diverse range of substituted thiophenes are used which enable the structure activity relationship. The compounds showed enhanced inhibition against MAO-A & B as compared to reference compounds. Compound 1c exhibited most potent MAO-A inhibition having IC50 value of 0.062 μM, while 1j showed excellent inhibitory potency against MAO-B having IC50 value of 0.088 μM. The present investigation demonstrated that among piperidyl-thienyl chalcones, almost all the compounds exhibit significant MAO-A inhibition, thus may have antidepressant activity. Whereas among the 2-pyrazoline derivatives of chal-cones, many compounds revealed MAOB inhibition and hence may be applied in the control of senile dementia. Molecular docking studies were carried out against human MAO-A and MAO-B to rationalize important binding site interactions.

In this investigation, the screening of two furanocoumarins; 5,8- dimethoxypsoralen (1) and heraclinin (2), isolated from the methanol root-extracts of Tamus communis L for their antioxidant activity and xanthine oxidase inhibitory effect was carried out, using different assays such as DPPH free radical scavenging effect, β- carotene / linoleic acid, xanthine oxidase (XO) inhibition and in addition to blood total antioxidant capacity. Results revealed that the two compounds have significant DPPH radical scavenging activity and effective inhibition of linoleic acid oxidation in a dose-dependent manner; 5,8-dimethoxypsoralen exhibited the highest activity with an I% = 72.69 ± 1.88 %. These results indicate that the isolated compounds inhibit xanthine oxidase activity and scavenge superoxide radicals with heraclinin (2) as the more potent xanthine oxidase inhibitor, and 5,8-dimethoxypsoralen (1) as the more effective on cytochrome c reduction, the two tested compounds can effectively protect erythrocytes against hemolytic injury induced by AAPH. These results are promising for further studies of the biological and pathological effects of these natural products.