Letters in Drug Design & Discovery - Volume 11, Issue 1, 2014

A new series of resveratrol acrylamides amine derivatives was designed, synthesized, and evaluated for their anti-proliferative activity against three cancer cell lines including human chronic myelocytic leukemia cell K562, human hepatoma HuH-7 and human lung carcinoma A549. Most of the compounds showed superior activity against three cell lines when compared to parent resveratrol. C13 had the best anti-tumor activity against the HuH-7 cell line and its IC50 was 4.5 μmol/L; C16 had the best anti-tumor activity against the K562 cell line and its IC50 was 2.9 μmol/L; C18 had the best anti-tumor activity against the A549 cell line and its IC50 was 3.8 μmol/L. It could be seen that the activity of the aromatic amine derivatives was better than the fatty amine derivatives by analyzing the experimental data.

Leucovorin is one of the several chemically active reduced derivatives of folic acid. It is used as an antidote to folic acid antagonist. Lecovorin calcium inj U.S.P. contains calcium folinate which belongs to a group of vitamins, used as an antidote to the harmful effects of Methotrexate (MTX) therapy. In this investigation, the modulatory effects exerted by the Leucovorin against MTX induced genotoxicity in mice by using Chromosomal Aberrations (CA) and sperm morphology assays were tested. Three different doses of Leucovorin were selected and tested for their modulatory activity on the genotoxicity exerted by 20 mg/kg of MTX. The results of the present study indicate a significant decrease in the frequency of CA and sperm head abnormalities suggesting that the Leucovorin modulates the MTX induced genotoxicity in a dose dependent manner and it reveals its antitoxic nature and suggests using along with chemotherapeutic agents in cancer chemotherapy. These findings provide the future directions for the research on design and development of possible modulatory drugs containing Leucovorin.

The in silico COMPARE analysis was performed on 8-[3-(piperidino)propyl]-4,10-dimethyl-9-phenyl-6- (methylsulfanyl)-3,4-dihydropyrimido[1,2-c]pyrrolo[3,2-e]pyrimidin-2(8H)-one, a compound with promising antiproliferative activity, previously synthetized and screened against a panel of 60 human tumor cell lines. The results evidenced that this compound matches the biological properties of Chromomycin A3 and Actinomycin D, known drugs with high DNA binding affinity. Prompted by such results, a thorough spectroscopic investigation of its DNA aqueous solutions was performed, with the aim to verify its DNA-binding properties. DNA groove-binding interaction was assigned by UV-vis spectrophotometric and circular dichroism (CD) titrations. In agreement with the spectroscopic studies, the test compound has achieved significant cell-cycle perturbation with higher accumulation of cells in G0/G1 phase. Further structure modifications of the tested compound, has led to its analogue, which showed DNA base-pairs intercalating ability. Molecular modeling studies on the annelated pyrrolo[3,2-e]pyrimidines tested were in agreement with the biological evaluation.

In view of the various and promising biological activities of gallic acid, we designed and prepared a series of poly-phenolic compounds carrying multi-gallic acids residues. These dimer and tetramer of gallic acids were facilely synthesized by convergent approach. Subsequently, antioxidant activity evaluation was carried out using DPPH assay, and the resulting polyphenol exerted enhanced activity to gallic acid monomer. Antiproliferative activity evaluation was performed using MTT assay with three human cancer cell lines (Hela, A549 and MCF-7) and two human normal cell lines (HEK293 and HUVEC). The cytotoxicity of the dimer and tetramer of gallic acid were higher than that of the monomer against both cancer and normal cell lines, however the cytotoxicity of the dimer and tetramer against cancer cells was much fiercer than normal cells, which resulted in better selectivity. Consequently, vanlency effects embodied in both antioxidant and antiproliferative activities of the obtained multi-gallic acid derivatives.

Virtual Screening (VS) methods can considerably aid clinical research, predicting how ligands interact with drug targets. However, the accuracy of most VS methods is constrained by limitations in the scoring function that describes biomolecular interactions, and even nowadays these uncertainties are not completely understood. In order to improve accuracy of scoring functions used in most VS methods we propose a hybrid novel approach where neural networks (NNET) and support vector machines (SVM) methods are trained with databases of known active (drugs) and inactive compounds, this information being exploited afterwards to improve VS predictions.

Cancer is a disease involving unregulated cell growth and grows uncontrollably forming malignant tumors, and invades nearby parts of the body. There are over 200 different known cancers that afflict humans. The chances of surviving this disease vary by the type and location. In 2007, cancer caused about 13% of all human deaths worldwide (7.9 million). In addition, various dietary phytochemicals having anticancer activity have been reported by certain in vivo and in vitro studies. The present work focus on the molecular docking simulation studies of a set of 32 dietary phytochemicals present in fruits, vegetables, legumes, whole grains and nuts reported of having anticancer property against Heat shock protein 90 (Hsp90). Hsp90 is an important promoter of oncogene addition and cancer cell survival. It is also secreted in large quantity and found on the surface of cancer cells. The main objective of this work involves the molecular docking simulation analysis and molecular descriptors analysis of the phytochemicals where the inhibitors showed competitive inhibition with ATP at the high-affinity ATP-binding site of Hsp90 enzyme. Thus preventing the ATP binding which eventually will block the function of this enzyme. Further, the docked analogues were screened for BioAssay activity at the NCBI PubChem database revealing three of the docked phytochemicals possessing strong anti cancer property. Lastly, these three phytochemicals were evaluated for ADME-Toxicity parameters.

MDM2 is the key negative regulator of p53 and an important validated target for anticancer drug discovery. Using the comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches, we performed LibDock based 3D-QSAR study on 42 isoindolinone derived MDM2 inhibitors for the first time. We found in CoMFA model including steric and electrostatic fields for the training set, the cross-validated q² value was 0.66 and the non-cross-validated r² value was 0.98, while, the cross-validated q² value was 0.58 and the noncross- validated r² value was 0.96 in CoMSIA Model. These results indicated that the CoMFA and CoMSIA analyses are very useful tools in the development of more potent p53-MDM2 binding inhibitors.

A quantitative structure–activity relationship (QSAR) of a series of acrylpimaric acid derivatives with antitumor activity on human lung cancer cells (NCI-H460) was performed by using CODESSA 2.7.15 software. Via a best multilinear regression analysis, the promising antitumor activity exhibited strong correlation with electrostatic and quantum-chemical descriptors of the compounds. According to the established QSAR equation, max net atomic charge for an N atom, min net atomic charge for an H atom, max net atomic charge for a C atom, tot hybridization composite of the molecular dipole, and number of occupied electronic levels of atoms are the most significant descriptors contributing to antitumor activity. This study provided significant insights that could be used in the further design of novel, potent inhibitors of NCI-H460.

The antifungal activity of a library of 32 cyclitols and derivatives, including 6 previously unreported cyclitol amino acid conjugates, was studied against the clinically important yeasts Candida albicans, Candida tropicalis and Cryptococcus neoformans along with Saccharomyces cerevisiae. Bioautography followed by standardized microbroth dilution methods were used and allowed to identify an azidoinositol glycoside (11) and an azidoconduritol linked to an aromatic aldehyde (18) as promising compounds. The results suggest the relevance of exploring synthetic cyclitolic structures as potential antifungal leaders.

The synthesis of twelve new pyrimidine hydrazone derivatives and subsequent evaluation of their antimicrobial activities were the aims of this present work. The intermediate product 2-[(pyrimidin-2-yl)thio]acetohydrazide was refluxed with different aromatic aldehydes/ketones in ethanol to yield N’-(arylidene)-2-[(pyrimidine-5-yl)thio]- acetohydrazide derivatives (3a-l). The structures of the compounds were elucidated by NMR, FTIR, MS, and elemental analyses. Additionally the final compounds (3a-l) were evaluated for their antimicrobial activity using a microdilution method against a panel of pathogenic Gram positive, Gram negative, and fungus strains, i.e. Escherichia coli, Pseudomonas aeruginosa, Salmonella typhimurium, Bacillus cereus, Bacillus subtilis, Serrratia marcescens, Staphylococcus epidermidis, and Candida utilis. Compound N’-(2-pyrilidene)-2-[(pyrimidine-5-yl)thio]acetohydrazide (3a) possessing a 2- pyridyl moiety was found to be the most active (MIC= 31.25-250 μg/mL) derivative toward the tested microorganisms.

Cyclooxygenase enzyme is a validated therapeutic target for designing drug molecules with anti-inflammatory activity. Herein, a series of various schiff base of 1,3,4-oxadiazole analogues were designed. Considering reasonable structural similarity of the target compounds with the commonly used anti-inflammatory drug indomethacin, it was decided to dock the target compounds into the active site of the molecular target of indomethacin. Prior to docking, the active sites of the proteins are identified. The docking study is performed using the UCSF DOCK 6.5 program. And also the utilization of principles involved in green chemistry is significantly reducing chemical waste and reaction times. To illustrate these advantages in the synthesis of bioactive oxadiazole derivatives, various environmentally benign protocols that involve greener alternatives were studied. The efficiency of microwave heating technology has resulted in remarkable reductions of reaction times (reduced from days and hours to minutes and seconds) with better product yield. The structures of newly synthesized compounds have been elucidated on the basis of IR, ¹H NMR, ¹³C NMR, LC-MS and elemental analysis. An evaluation of the anti-inflammatory activity of the prepared compounds has indicated that some of them exhibited moderate to significant activity as compared to indomethacin.

We have evaluated as sodium channel blockers a series of imidazobenzoxazines, imidazobenzoxazin-5-ones and imidazobenzoxazin-5-thiones. We tested these new compounds on NaV1.6 and NaV1.2 sodium channel isoforms, that are expressed in central nervous system and seems to be very important in controlling neuronal firing. Moreover, mutations in SCN2A, the gene encoding NaV1.2, have been identified in patients with generalized epilepsy. Almost all of the new molecules were able to block the NaV1.6 sodium currents and some of them displayed IC50 values in the low micromolar range.

A series of salicylic acid-oriented thiourea derivatives was conveniently synthesized via multi-steps mainly including alkylation, chlorination, nucleophilic substitution and addition reaction. The structure of all these newly synthesized derivatives was confirmed and characterized by IR, ¹H NMR and MS. The preliminary bioassay indicated that these new compounds have some herbicidal activity or plant growth regulating activity against tested plants.

7-Aryl substituted furo[3,2-h]quinoliniums have been synthesised in two steps from 5-chloro-8-hydroxy-7- iodo-quinoline through a tandem Sonogashira alkynylation-cyclization pathway using aryl acetylenes followed by quaternisation reaction with alkyl halides under microwave irradiation. The compounds have been characterized spectroscopically and assessed for their sperm-immobilizing efficacy in vitro by modified Sander–Cramer test. Most of the derivatives showed potent spermicidal effect with minimum effective concentration (MEC) ranging from 125g/ml – 1mg/ml. The results were further confirmed by double fluoroprobe staining with syber14/PI (Propidium Iodide). The mode of spermicidal action was assessed by (a) Hypo-osmotic swelling tests and (b) Scanning electron microscopy. The compounds have been found to be nontoxic to lactobacillus in 36 hours of culture whereas mild to moderately effective on common vaginal pathogens. Taken together it can be inferred that the water-soluble salts prepared from facile technique are potential candidates for spermicides and could further be utilized for the preparation of vaginal contraceptives.

The arylation of 4-iodo-, 2-iodo- and 3-iodophenols with 2-fluorobenzaldehyde may be carried out in the presence of K2CO3 in DMF as the solvent under microwave conditions. The arylation of 4-iodophenole was promoted by the use of triethylbenzylammonium chloride (TEBAC) as the phase transfer catalyst. In the other model reactions, the use of TEBAC was harmful. By-products formed by isomerization and disproportionation were also detected.