Letters in Drug Design & Discovery - Volume 8, Issue 1, 2011

Molecular modelling studies of complexes of 2-phenylamino-6-oxopurines and HSV1 thymidine kinases (TK) revealed two distinct modes of binding. The “acyclovir mode” was occupied by 9R (9-substituted) compounds, and was identical to that revealed by crystal structures of acyclovir and 2-phenylamino-9-(4-hydroxybutyl)-6-oxopurine (HBPG) bound to HSV1 TK. The “base mode” was occupied by 9H compounds such as 2-[3-(trifluoromethyl)phenylamino]-6- oxopurine (m-CF3PG) , and is characterized by rotation of the inhibitor by 180° around the minor axis of the purine ring. In an attempt to understand the molecular basis for affinity of 2-phenylamino-6-oxopurines for TKs, we cloned and expressed site-directed HSV2 TK mutants to create proteins with inhibitor-interacting domains identical with those of HSV1 TK. The enzyme kinetic properties and inhibitory action of several 2-phenylamino-6-oxopurines showed that the changes were not consistently correlated with differences in affinity of inhibitors to the TKs.

Src has been recognized as an important therapeutic target for the treatment of cancer. A novel series of triazole- based Src inhibitors were synthesized and evaluated for their anti-proliferative activities in vitro against human lung cancer A549 cells with Bosutinib as reference compound, most of the compounds showed more potent activity than Bosutinib. Compounds 6 and 8 were further subjected to pharmacokinetic performance assessment, both the compounds displayed low plasma concentrations and short half-time.

A QSAR analysis of 25 isosteviol derivatives was carried out to interpret the relationship between structural properties and α-glucosidase inhibitory activity. The selected significant models have good predictive ability, which was validated by LOO cross validation techniques (Q2>0.6) and which gives significant Cook's distances (<1) and other statistical parameters. The selected significant models suggest that the nitrogen count amongst those that contribute most to α- glucosidase inhibitory activity is positively accounted for activity. Besides nitrogen count, the XlogP (by Kellog method) and the SlogP (by Audry method) mosthydrophobichydrophilic distance descriptors also contribute positively and the Quadrupole2, Avg+P and SAMH parameters are negatively contributed for the activity while a triple bonded atom connected with another triple bonded atom by four or seven bonds distance is important for the activity. In conclusion, the presence of nitrogen atom along with the hydrophobic-hydrophilic distance in the molecule is important for the α- glucosidase inhibitory activity.

We report the tentative initial results of our on-going search for potent inhibitors of estrone sulfatase (ES), here we report a series of alkyl 6-aminosulfonyl naphthanoate-based compounds as potential inhibitors. The results suggest that the compounds are weak inhibitors in comparison to the standard compound used within the current study.

The FLAP inhibitory activity of 2,2-bisaryl-bicycloheptane derivatives has been quantitatively analyzed in terms of Dragon descriptors. The derived QSAR models have provided rationales to explain the FLAP inhibitory activity of 2,2-bisaryl-bicycloheptane derivatives. The presence of quinolinylmethoxy substituent at R2-position in a molecular structure is a crucial feature for the FLAP inhibitory activity. The occurrence of R-CR-X type structural fragment (descriptor C-028) and higher number of sulfur atoms (descriptor nS) in a molecular structure are prevalent to rationalize the FLAP actions of bicycloheptane derivatives. The topological charge indices (descriptors GGI3, 3rd order Galvez topological charge index; and JGI4, 4th order Galvez mean topological charge index), path/walk ratio 2 (Randic's molecular shape descriptor PW2) and atomic polarizabilities at lag 2 (descriptor GATS2p, Geary autocorrelation of lag 2 weighted by atomic polarizabilities) are also important to explain the FLAP activity. The PLS analysis has also confirmed the dominance of information content of CP-MLR identified descriptors. Applicability domain analysis revealed that the suggested model matches the high quality parameters with good fitting power and the capability of assessing external data, and all of the compounds were within the applicability domain of the proposed models and were evaluated correctly.

Various significant anti-HCV and cytotoxic sesquiterpene lactones (SLs) have been characterized. In this work, the chemometric tool Principal Component Analysis (PCA) was applied to two sets of SLs and the variance of the biological activity was explored. The first principal component accounts for as much of the variability in the data as possible, and each succeeding component accounts for as much of the remaining variability as possible. The calculations were performed using VolSurf program. For anti-HCV activity, PC1 (First Principal Component) explained 30.3% and PC2 (Second Principal Component) explained 26.5% of matrix total variance, while for cytotoxic activity, PC1 explained 30.9% and PC2 explained 15.6% of the total variance. The formalism employed generated good exploratory and predictive results and we identified some structural features, for both sets, important to the suitable biological activity and pharmacokinetic profile.

The novel phosphorylated derivatives of Lamivudine (5a-5l) as potential anti colon cancer agents are synthesized. These title compounds are designed based on the basic pyrimidine derivative lamivudine as a starting compound and reacted with various phosphorodichloridates followed by the introduction of bioactive groups at the phosphorus. Their structures were characterized by IR, 1H, 13C, 31P NMR and mass spectral analyses. All the compounds were evaluated for their anti colon cancer activity against COLO-205 cell lines in vitro studies. Among them 5a and 5b emerged as lead compounds with 0.003 μM and 0.0001 μM values.

Mutant selection window (MSW) is the antimicrobial concentration ranging from the minimum inhibitory concentration (MIC) to the mutant prevention concentration (MPC). Placing antibiotic concentration in the MSW is expected to selectively enrich mutant subpopulations while placing the concentration above the window is expected to restrict the selective enrichment of resistant bacteria. Even though there is a rise of multidrug resistant bacteria, there are not many new antibiotics introduced to market in the recent years. Therefore, there is a need to utilize existing knowledge on antibiotics to prevent the development of multidrug resistance and if possible reposition the antibiotics. The increase in knowledge on MSW and microbial evolution of resistance can be of potential use in novel dosing regimens and antimicrobial combinations. In this study, we investigated the effect of the addition of ethyl gallate (EG) on the MSW and MPC of MRSA ATCC strain 43300, before and after it has been induced to develop resistance to tetracycline and fusidic acid. It is observed that tetracycline has narrower MSW than fusidic acid. This suggests that fusidic acid provides less genetic stability than tetracycline and hence it is easy for mutants to develop. We also report that addition of ethyl gallate at 1024μg/ml closes the mutant selection window (i.e. MIC = MPC) of both tetracycline and fusidic acid, thus helping overcome the effect of resistance developed over time. Hence, we propose that combination of ethyl gallate with antibiotics has potential clinical implications and needs further exploration.

This study was designed to assess the effect of honey supplementation and sugar-based hypercaloric regimen on weight gain and blood pressure (BP) in Wistar rats. Animals were fed for 8 weeks with standard diet (S-free) or a hypercaloric diet (standard chow and 30% sugar in drinking water), (SF), or standard chow supplemented with fat and honey and 10% sugar in drinking water (HF). Overall weight gain and body fat levels were significantly higher in SF and HF than in S-free. Fat cells were significantly larger in SF compared with HF. Compared with SF and S-free, HF had higher glucose, but triglycerides, and LDLc levels were not different. BP was significantly higher in SF but not in HF compared to S-free. These observations indicate that honey may afford a protection against increase in BP and in fat cell size resulting from a hypercaloric diet.

TRPV1 is a ligand-gated non-selective cation channel that is considered to be an important pain integrator. Capsaicin, the prototypical TRPV1 agonist, has a clear therapeutic potential. In this letter, for lowering its pungency, a series of nitric oxide-releasing derivatives of capsaicin were designed and synthesized, including 10 compounds which were the direct combination of capsaicin and dihydro capsaicin with various nitric oxide donors. Preliminary biological tests suggested the compounds had both TRPV1 agonist activity and nitric oxide release activity. Compound B2, B5, B8 had better analgesic activity than capsaicin. Based on these results, Compound B2, B5, B8 can be considered as lead candidates for the further development of analgesic drugs.

A series of 1,3-thiazolidin-4-one derivatives were prepared by the reaction of respective aromatic amine, aromatic aldehyde and thioglycolic acid in dry benzene/toluene. The newly synthesized compounds were characterized on the basis of elemental analysis, IR, 1HNMR and mass spectra. The newly synthesized final compounds were evaluated for their in-vitro antibacterial, antifungal and anti-viral activities. Preliminary results indicated that most of the compounds demonstrated moderate to good antimicrobial activity, comparable to standard drugs. Structure-activity relationship studies revealed that the nature of the substituents at the 2nd and 3rd positions of the thiazolidinone nucleus had a significant impact on the in-vitro antimicrobial activity of this class of potent antimicrobial agents.

Methylnaltrexone (MNTX) is a peripherally-acting opioid receptor antagonist. Since it has restricted access to the blood-brain barrier, MNTX has the ability to decrease opioid-induced constipation without affecting the analgesic effects of opioid pain medications. MNTX has a limited gastrointestinal absorption and currently, only subcutaneous MNTX is clinically available to help restore bowel function in patients with late-stage advanced illness who are receiving opioids. A MNTX emulsion (MNTX-EM) formulation was prepared in this study to improve the oral bioavailability of the compound. A sensitive liquid chromatography-tandem mass spectrometry (LC/MS/MS) method was established and validated for the determination of MNTX plasma concentrations. With an extended linear range of 1 to 1000 ng/mL, this assay was specific, precise, and accurate. Following 110 mg/kg oral administrations of unformulated methylnaltrexone water solution (MNTX-WS) and MNTX-EM in rats, plasma samples were collected for up to 9 h and MNTX levels were measured. The plasma MNTX concentrations after MNTX-WS and MNTX-EM were compared. Data showed that there were two MNTX concentration peaks after both MNTX-WS and MNTX-EM. For the first peak, the peak plasma concentration (Cmax) and the area under the concentration curve (AUC) from 0 to 60 min for MNTX-WS and MNTX-EM were 210.0 ng/mL, 87.2 ng•h/mL and 390.2 ng/mL, 321.9 ng•h/mL, respectively (both P < 0.01). For the second peak, Cmax and AUC from 60 to 420 min for MNTX-WS and MNTX-EM were 172.7 ng/mL, 663.4 ng•h/mL and 597.6 ng/mL, 1941.7 ng•h/mL, respectively (both P < 0.01). The relative bioavailability after oral administration of MNTX-EM was 302% compared to that of MNTX-WS. These results suggested that the emulsion formulation might be clinically useful in enhancing the oral absorption of MNTX.

Drug discovery in the field of oncology has been advanced mainly through the targeting of receptor tyrosine kinases. Both antibodies and small molecule inhibitors have been found to have successful applications in blocking the proliferative functions of these cell surface receptors. Based on these early successes, additional kinases within the cytoplasm have been found to promote cancer and, as such, have been recognized as feasible targets for additional modes of therapies. Unlike these oncogene targets, most tumor suppressors are irreversibly altered during cancer progression and therefore are not feasible targets for therapy. However, a subset of these genes is reversibly epigenetically suppressed. One such gene is BRM, and when it is re-expressed in cancer cells, this gene halts their growth. Moreover, as the key catalytic subunit of the SWI/SNF complex, BRM is centrally important to a host of anticancer pathways and cellular mechanisms, and its status may serve as a biomarker. Restoring its expression will both reconnect a number of growthcontrolling pathways and affect cellular adhesion, DNA repair, and immune functions. For these reasons, restoring BRM expression is not only feasible, but potentially a potent form of anticancer therapy. To identify BRM-restoring compounds, we developed a cell-based luciferase assay. In this review, we discuss some of the challenges we encountered, issues related to this type of drug discovery, and our future ambitions. We hope this review will provide insight to this type of endeavor and lead to more investigations pursuing this type of drug research.