Letters in Drug Design & Discovery - Volume 8, Issue 7, 2011

Hydroxyurea (HU) has been used as a therapeutic agent for many years. It is an effective inhibitor of ribonucleotide reductase possessing drawbacks with toxicity and resistance. Efforts have been made to modify the structure to eliminate or minimize these therapeutic drawbacks and we recently developed a novel two step protocol for the synthesis of mono and di-substituted hydroxy ureas. Modeling and apoptotic studies of a series of seven synthesized analogs were undertaken with the effort to design a better inhibitor for ribonucleotide reductase. While cell studies showed a difference in activity of these HU analogs, with the α-napthyl analog being a better inducer of apoptosis than the parent HU, an initial examination of the analogs did not show a clear reason for this result. Molecular modeling studies that were carried out using AM1 suggest that the difference in activity can be correlated with the energetics associated with rotation barriers around the N-C-N-O torsion angle. These studies also showed a difference in charge at the terminal of oxygen and nitrogen which differentiates the α-napthyl HU. In addition, the HU backbone of the α-napthyl analog is electrostatically the most consistent with the parent HU. Modeling of the analogs in the active site of ribonucleotide reductase suggests that the activity of the active analog may be due to its ability to adjust conformationally to fit the required interactions in the active site as a result of its low energy barrier to rotation.

A classification structure-activity relationship study has been carried out using topological indices, physicochemical and steric parameters on a series of 1-[2-hydroxyethoxy-methyl]-6-(phenylthio) thymine for their HIV reverse transcriptase inhibitory activity. The predictive classification performance of support vector machines method is investigated and compared with those of other classifiers such as artificial neural networks, linear discriminant analysis, k-nearest neighbours and decision trees. This paper discusses several validation strategies including randomization test, internal and external validations. The quality of the models was evaluated by the number of right classified compounds. The results obtained show that all methods used except k-nearest neighbours were good classifiers. The percentage of right classified compounds ranges from 87.7% to 95.4% and from 64.3% to 92.9% for the training and test sets, respectively. The relevant factors controlling the anti-HIV activity have been identified. The descriptors related to both steric characters (6Xvch, 4XNP and 1/S) and hydrophobic parameter (logP) seem to be very relevant in the establishment of structure-anti- HIV activity relationship.

A series of novel phenylamino-pyrimidine derivatives were designed and synthesized as antitumor agent based on the lead compound of Imatinib by application of the principle of bioisosterism, hybridization and structural optimization. The bioactivities of the new target compounds were tested against human KU812 cells in vitro, some target compounds show promising activities and can be considered for further development.

In continuation of our program aimed at the discovery and development of anti-HIV-1 agents, six 1-hydroxy-4- chloro-9, 10-anthraquinone derivatives (3-8) were prepared and preliminarily evaluated as HIV-1 inhibitors in vitro for the first time. Compounds 4 and 6 exhibited the potent anti-HIV-1 activities with EC50 values of 9.81 and 17.90 μg/mL, and TI values of >13.58 and >11.17, respectively. It demonstrated that introduction of the alkylacyloxy or alkylsulfonyloxy group at the 1-position of 1-hydroxy-4-chloro-9,10-anthraquinone could afford the more promising and potent compound than that having arylacyloxy or arylsulfonyloxy one.

A series of N-benzyl-9(10H)-acridinones were synthesized and tested for their antitumor activities in vitro against HepG2 cells.Assay-based antiproliferative activity study using HepG2 cell lines revealed that several compounds had significant effects on cytotoxicity, among which compound 5h was found to be the most active compound with IC50 at about 1.33 μM using the MTT assay. The antitumor effect of compound 5h is believed to be due to the induction of apoptosis, which was further confirmed by Hoechst 33258 fluorescence staining, agarose gel electrophoresis and Annexin VFITC/ PI staining assay using flow cytometry analysis. Above all, compound 5h would be a potential anticancer agent which deserves further research.

A series of (Z)-5-arylidene-4-thioxo-thiazolidine-2-ones (4a-o) were synthesized using microwave irradiation technique. The structures of the newly synthesized compounds were confirmed by IR, 1H NMR, 13C NMR spectral studies and elemental analysis. All compounds were evaluated for their preliminary in vitro antimicrobial and cytotoxic activities. The investigation of antimicrobial activity profile revealed that compounds 4d, 4f, 4g, and 4h exhibited marked activity against S. aureus and E. faecalis as compared with the standard while compounds 4d and 4h exhibited good antifungal activities against C. albicans, A. flavus, A. niger and C. neoformans. In preliminary MTT cytotoxicity studies, the (Z)-5- arylidene-4-thioxo-thiazolidine-2-one derivatives (4k, 4l and 4m) were found most potent. Compound 4m inhibited proliferation of HeLa, HT29, A549 and MCF-7 cell lines with an IC50 values of 23, 22, 20 and 20 μM, respectively.

Fatty acid biosynthesis in the Aeromonas hydrophila plays an important role in the formation of cell membrane and cell viability. The 3-oxoacyl- acyl carrier protein (ACP) synthase fadH and fadB from A. hydrophila have contributed in the initiation and elongation of fatty acid biosynthesis. In this study, we have designed new set of primers for amplification of the open reading frame of fadH and fadB. Cloning and sequencing of these amplified genes, analyzed that the G+C content of fadH and fadB were 63.3% and 68.79% respectively. The homology modeling was performed to generate the 3- D structure of fadH and fadB; and showed that more than 90% amino acid residues in allowed region of Ramachandranan plot. These findings provide a new avenue for better understanding, the role of genes encoding proteins involved in the fatty acid biosynthesis and thereby using as a potential and novel target for structure based drug designing to control the infections of A. hydrophila.

New anacardic acid derivatives (6a -6u) were prepared from commercially available anacardic acid and tested for Gram positive and Gram negative activities. Most compounds were found to be active compared to ampicillin.

Efficient synthesis of 4H-pyrimido[2,1-b]benzothiazoles by novel one-pot three-component reaction of an aldehyde, β-ketoester and 2-aminobenzothiazole using sulphamic acid as a catalyst is described. All synthesized compounds were evaluated for in vitro antibacterial activity using Gram-positive bacteria and Gram-negative bacteria (Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa , Bacillus subtilis, Proteus Valgaris). In vitro antifungal activity was also determined against the five fungal species (Aspergillus flavus, Candida albicans Aspergillus fumigatus, Penicillium mareneffei, Chrysosporium tropicum). Structure of the synthesized compounds was established by elemental analysis and spectral data.

In this study, 2-chloroquinolin-3-carbaldehyde 1 was used as a synthon for the synthesis of some new quinoline; pyrane; indeno[1,2-b]pyrano[2,3-b]quinoline heterocycles. The anti-inflammatory and analgesic activities of the synthesized compounds were evaluated using carrageenan-induced paw edema and writhing assays. The obtained data indicated that the majority of the tested compounds exhibited both analgesic and anti-inflammatory activities, particularly compounds 2 and 6 showed a comparable effect to a well known analgesic and anti-inflammatory, diclofenac sodium.

The solid-phase synthesis of di-N-acetyl-β-chitobiosyl NAG (N-acetyl D-glucosamine)-thiazoline 3 was reported. After the 6-O-benzyl NAG-thiazoline 9, NHCbz trichloroacetimidate donors 14, and 21 were synthesized, and solid-phase synthesis was performed using the Wang resin as support. The target di-N-acetyl-β-chitobiosyl NAGthiazoline 3 was obtained by iterative glycosylation reactions, catalytic hydrogenation, acetylation, and deacetylation, respectively.

To study the drug-like features and ADME properties of Tongguan Capsule (TGC), a Traditional Chinese Medicine (TCM) for coronary heart disease (CHD). A systemic computational pharmacology approach about pharmacokinetic (PK) modeling was introduced to investigate the global nature of TGC, including chemical space distribution, prediction of ADME and construction of network. As a result, the natural components from TGC had similar chemical properties with synthetic drugs; prediction of ADME for TGC afforded an initial and plain view on the metabolism and safety through a macroscopic and holistic view, which involves complicated processes and mechanisms in vivo; the networks make the chemical similarity between natural components and synthetic drugs well visualized. Therefore, Computational approaches can promote our understanding on complex components and bioactivity, even the mechanism and metabolizing process in vivo of TGC.

In an effort to develop a quantitative ligand-binding model for the CB1R, pharmacophore modelling studies were performed on 1-sulfonyl 4-acylpiperazine derivatives. Pharmacophore Alignment and Scoring Engine (PHASE) was used to develop predictive Common Pharmacophore Hypotheses (CPHs) in which a five point pharmacophore with one hydrogen bond acceptor (A), two lipophilic/hydrophobic groups (H) and two aromatic rings (R) as pharmacophoric features was developed. On the basis of statistical values, the best-fitted model was identified and the same alignment was used for CoMFA and CoMSIA studies. The models developed showed an excellent r2 predictive value of 0.879 for CoMFA and 0.764 for CoMSIA. The robustness of the models was validated and the mean activity for test set compounds can estimate external predictivity. The 3D contour maps generated from CoMFA/CoMSIA offer important structural insights and provided interpretable explanation of SAR for the compounds. The obtained results may help in designing analogs with better activity.