Letters in Drug Design & Discovery - Volume 7, Issue 2, 2010

Conventional chemotherapy of intracellular infections often fails due to the low uptake of commonly used antibiotics or to their reduced activity at the acidic pH of lysosomes. With the aim of improving the therapeutic action of metronidazole against intracellular infections along with an overcome of their important drawbacks, we investigated its incorporation into a drug delivery nanosystem based on the biodegradable polymer chitosan. The formulation of this polymeric colloid assured a high electric surface charge and a great hydrophobicity, which are known to be two important characteristics determining an intense and non-specific recognition by the mononuclear phagocyte system (i.e., rapid uptake by infected phagocytes). Two metronidazole loading procedures were investigated: i) drug surface deposition or adsorption method onto already formed nanoparticles; and ii) drug absorption or entrapment into the polymeric matrix: incorporation of metronidazole prior to the coacervation process that leads to the formation of chitosan nanoparticles. Such polymeric colloid hold very significant characteristics (high drug loading and little burst release, hydrophobicity and high surface charge), suggesting its potential application for an efficient metronidazole delivery to intracellular infections.

(±)-Trans-Ph/Et and (±)-cis-Ph/Et 1-(2-ethyl-1-phenylcyclohexyl)piperidine were synthesized from 2-ethylcyclohexanone. In contrast to the corresponding trans-substituted 2-methyl compound which is 5x more potent than PCP, the trans-2-ethyl derivative has a 75x lower affinity for the PCP binding site. The cis-2-ethyl isomer is inactive like the cis-2-methyl derivative. (±)-1-(1- Phenylcyclohexyl)-2-methylpiperidine is almost as active as the parent PCP. Reduction of the aromatic ring or quaternization of the piperidine in PCP reduces the affinity for the PCP site.

We examine trends in binding strength and activation barriers of four polyunsaturated fatty acids in the cyclooxygenase active site of PGHS-1 that influence the relative rates of oxygenation. A Natural Bond Orbital analysis at the B3LYP/6-31G level of theory is used to determine that the overall binding strength. Relative barriers for the rate-determining step are calculated at the B3LYP/3-21G level of theory.

Methotrexate (MTX) use associated with optical irradiation of the malignant tumours requires knowledge of its intratumoral retention time. Radioactive Chromatography and absorption spectroscopy confirm synthesizing of 2,4 diamino 6-pertechnetate pterine that pursues MTX biodistribution. Sequential scintigraphy shows an intratumoral MTX retention time of one hour from systemic administration in bolus.

A series of seventeen N4-substituted 5-nitroisatin-3-thiosemicarbazones 2a-2q has been synthesized and screened for in vitro urease inhibitory activities. Compounds 2a-2d, 2g, 2i, 2j and 2q were found to be potent inhibitors of the enzyme. Of these, 2c exhibited a potent inhibitory activity with IC50 value 16.4 μM and may act as a lead molecule for further studies. Structure-activity relationship studies revealed that electronic effects of the substituents play an important role in the urease inhibitory potential of the synthetic compounds.

A series of novel 1-benzhydryl-4-(3-(piperidin-4-yl)propyl)piperidine sulphonamide derivatives 8(a-j) was synthesized in good yield and met the structural requirements essential for anticonvulsant properties. The structures of the synthesized compounds were confirmed on the basis of their spectral data and elemental analysis. All the compounds were evaluated for their possible anticonvulsant activity by Maximal Electroshock Seizure (MES) test and their neurotoxic effects were determined by rotorod test. Majority of the compounds were active in MES tests. Compounds 8f and 8g have shown a significant and protective effect on seizure, when compared with standard drug phenytoin. Compound 8f and 8g without a fluoro group showed anticonvulsant activity in MES test as compared with compound 8a and 8b with fluoro substituents. From this study, it is quite apparent that there are at least three parameters for the activity of anticonvulsant drugs, that is, a lipophilic domain, a distal hydrophobic center and two-electron donor (-C-N=) system.

Synthesis and evaluation of C-28 oleanolic acid derivatives as novel inhibitors of glycogen phosphorylase have been described. The results of glycogen phosphorylase inhibition assay and structure-activity relationship (SAR) analysis are also discussed.

TRPV1 is an important analgesia target. Capsaicin, the prototypical TRPV1 agonist, has a clear therapeutic potential. But the highly pungency limited its use. In this letter, for lowering its pungency, a series of capsaicin derivatives were designed and synthesized, including 10 compounds which were the direct combination of capsaicin and dihydro capsaicin with various NSAIDs. Preliminary biological tests suggested that some compounds had both anti-inflammatory activity and analgesic activity and their pungency was lower. Based on these results, some of these molecules can be considered as lead candidates for the further development of analgesic drugs.

Ring substituted imidazoles are the emerging class of antitubercular agents. CoMFA model for various ring substituted imidazoles is used to elucidate their structure activity relationships. Both the training set and test set compounds were modeled to the established procedures and were aligned. There was a good correlation between the predicted and experimental activities for both the test set and training set compounds by CoMFA model. Structure activity relations have been established based on the obtained contour maps from the 3D-QSAR analysis.

Peripheral benzodiazepine receptor (PBR) is an important target for the development of drugs to treat anxiety and sleep disorders. Hologram QSAR models were built for good statistical results. Contribution map analysis explains the individual atomic contributions to the overall activity. This HQSAR model should be useful for the further development of novel structurally related PBR ligands.

Hepatitis C virus (HCV) is a major human pathogen, infecting an estimated 170 million persons worldwide, roughly five times the number infected by HIV type 1. A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma. The current treatment regimen suffers from various side effects. These limitations encourage the search of more effective HCV inhibitors. To achieve this objective a quantitative structure-activity relationship (QSAR) study has been made on three different series of anti-HCV agents that are comprised of pyrrolo[2,3-d]pyrimidine nucleoside derivatives, benzimidazole-coumarin conjugates, and ribonucleoside analogues, respectively. The QSAR analysis reveals that anti-HCV potencies of these series of compounds are controlled by a topological parameter (Kier's first order valence molecular connectivity index 1χv), lipophilicity, and the molar refractivity of the compounds, respectively. Based on these results, the mechanisms of drug-receptor interactions of these compounds are discussed, which may be of great help to design and develop more anti-HCV agents.