Medicinal Chemistry - Volume 9, Issue 1, 2013

Novel 6-ketolevorphanol analogs with diverse substitution patterns at ring C were synthesized and their binding affinities at the μ,δ and κ opioid receptors were investigated. The in vitro activity of the new analogs was then evaluated in the functional assay based on the electrically-stimulated contractions of the mouse ileum. It was shown that analogs with Δ7,8 bond had no significant potency at any of the opioid receptor types. In contrast, analogs with the saturated ring C were either potent κ agonist or antagonist depending on the absence or presence of the hydroxyl group in position 14.

A new multidentate ligand (L) has been synthesized by the controlled condensation of L-glutamic acid with formaldehyde and ethylenediamine. Cu(II) and Ru(III) metal ion complexes of the synthesized ligand have also been prepared. The ligand and the metal complexes were purified by chromatography and characterized by spectroscopy and other techniques. Molar conductance measurements suggested ionic nature of the complexes. The ligand and the complexes are soluble in water with quite good stabilities; essential requirements for effective anticancer drugs. DNA binding constants (Kbs) for copper and ruthenium complexes were 1.8 x 103 and 2.6 x 103 M-1 while their Ksv values were 7.9 x 103, and 7.3 x 103; revealing strong binding of these complexes with DNA. Hemolytic assays of the reported compounds indicated their significantly less toxicity to RBCs than the standard anticancer drug letrazole. Anticancer profiles of all the compounds were determined on HepG2, HT-29, MDA-MB-231 and HeLa human cancer cell lines. All the compounds have quite good activities on HeLa cell lines but the best results were of CuL on HepG2, HT-29 and MDA-MB-231 cell lines.

MCH1R antagonists have been used to treat several diseases, such as obesity, depression and anxiety. In this study, we have performed several pharmacophore-based CoMFA studies for a series of 2,4,6 substituted quinolines as potent antagonists of MCH1R. Significant statistical results were obtained (q2 = 0.78, r2 = 0.99), indicating the high internal consistency of the 3D model generated, as well as its predictive power for untested compounds. The 3D model was externally validated employing a test set and the predicted biological values showed good agreement with experimental results. Important insights on the molecular interactions between the studied ligands and the MCH1R receptor, inferred from the 3D contour maps, were obtained and can be useful for the design of new structurally related analogs with improved binding affinity.

In this paper, VSTPV, was recruited as a novel set of structural and topological descriptors derived from principal component analysis (PCA) on 85 structural and topological variables of 166 coded and non-coded amino acids. By using partial least squares (PLS), we applied VSTPV for the study of quantitative structure-activity models (QSARs) studies on two peptide panels as 101 synthetic cationic Antimicrobial polypeptides (CAMELs), and 28 bovine lactoferricin- (17-31)-pentadecapeptides (LFB). The results of QSARs models were superior to that of the earlier studies, with squared correlative coefficient R2 and cross-validated Q2 of 0.783, 0.656; and 0.864, 0.793, respectively. So, VSTPV descriptors were confirmed to be competent to extract information on 85 structural variables and to relate with biological activities.

A remarkable diastereoselective synthesis of some novel arylthiazolyl pyrazoline derivatives 3(a-l) is displayed which were evaluated for their in vitro antimicrobial activities. In particular, compounds 3e, 3g & 3l (MIC 12.5 μg /ml) showed good activity against S. aureus and compounds 3b & 3j (MIC 12.5 μg / ml) against B. subtilis. Compounds 3g, 3i, 3j (MIC 12.5 μg/ ml) and 3l (MIC 6.25 μg / ml) also displayed excellent antifungal activity against C. albicans. Of all the synthesized compounds, 3g and 3e exerted a wide range of antibacterial activities against entire tested gram positive (S. aureus and B. subtilis) and gram negative (E. coli and P. aeruginosa) bacterial strain except P. aeruginosa.

A series of N2-acyl isonicotinic acid hydrazides (1-17) was synthesized and tested for its in vitro antimycobacterial activity against Mycobacterium tuberculosis and the results indicated that the compound, isonicotinic acid N'- tetradecanoyl-hydrazide (12) was more active than the reference compound isoniazid. The results of antimicrobial activity of the synthesized compounds against S. aureus, B. subtilis, E. coli, C. albicans and A. niger indicated that compounds with dichloro, hydroxyl, tri-iodo and N2 -tetradecanoyl substituent were the most active ones. The antiviral activity studies depicted that none of the tested compounds were active against DNA or RNA viruses. The multi-target QSAR model was found to be effective in describing the antimicrobial activity of N2-acyl isonicotinic acid hydrazides.

Siderophores are small molecules produced by bacteria under iron-scarcity conditions faced by bacteria inside host. Sideophores bind iron with high affinity (Kd < 10-25 M) and are required for iron transport into the bacterial cell. Small molecules interfering with siderophore functioning can be promising anti-mycobacterial agents. Several molecules with hydrazone as a structural feature are known to have metal chelating property. This prompted us to investigate the metal chelating ability of 2-hydrazino-pyrimidin-4(3H)-one derivatives. In this light, a library of 22 novel molecules with 2- hydrazino-pyrimidin-4(3H)-one moiety was synthesized and the compounds were evaluated against M. tuberculosis under iron-limiting and iron-rich conditions. Interestingly, several molecules showed promising (MIC:<10 μM) selective activity under iron scarcity conditions. Furthermore, compounds were found to be nontoxic at lower concentration in VERO cell lines using MTT assay. Taken together, we have discovered novel 2-hydrazino-pyrimidin-4(3H)-one molecules active against M. tuberculosis which can be developed as potent antimycobacterial agents.

5-Arylidene-2-oxo-4-thiazolidinones and 2-phenylimino analogues were evaluated for their antidegenerative activity on human chondrocyte cultures stimulated by IL-1β and for their inhibitory capability against matrix metalloproteinase- 13. Our results indicated that 5-arylidene-4-thiazolidinone derivatives 1-9 exhibit antidegenerative activity and could block multiple cartilage destruction during the osteoarthritic process. Out of the selected compounds, (5-arylidene- 2,4-dioxothiazolidin-3-yl)acetic acids 7-9 showed significant effectiveness in reducing NO release and restoring normal levels of GAGs in chondrocytes treated with IL-1β. Moreover, benzoic acids 1, 5 and 6 proved to be effective MMP-13 inhibitors and were able to restore normal levels of GAGs.

P38 mitogen activated protein kinases have been found to involve in the production and release of unwarranted levels of pro-inflammatory cytokines including TNFα and IL-1β in numerous inflammatory diseases. A new series of molecules, 5-substituted benzoylamino-2-substituted phenylbezimidazoles has been synthesized from 4-nitro-1, 2- diaminobenzene. The synthesized compounds were characterized by FTIR, 1HNMR and Mass. The final compounds were screened for in vitro p38 kinase inhibitory and in vivo anti-inflammatory activity. Three compounds from the series demonstrated nearly 50% inhibition of p38 kinase in the in vitro screening method at 10 μM concentration and two molecules exhibited greater than 75% inhibition of paw oedema volume during the first hour. The docking study of synthesized molecule revealed a new binding pose in ATP binding pocket.

New compounds with hydrophyllic esters of (-)-carinol were synthesized and evaluated as xanthine oxidase enzyme inhibitors and antioxidants. Aliphatic esterfication of C-9,9'-OH groups of (-)-carinol resulted in lowering antioxidant and xanthine oxidase inhibitory activities. However certain aromatic acyl esters considerably improved the xathine oxidase inhibition. Aromatic esterification with electron withdrawing substitutions would preferred for improvement in XOD inhibition while retaining radical scavenging activity, electron withdrawing substitution led to the loss of free radical scavenging property and neutral substituents decrease the enzyme inhibitory potential.

With a view to develop novel non-TZD anti-diabetic compounds, series of isoxazolidinediones were designed to target the PPAR-γ receptors. Docking studies were performed on co-crystallized protein structure of rosiglitazone with PPAR-γ receptor obtained from Protein Data Bank (2PRG). Interactions similar to that of rosiglitazone were observed for three molecules; 3a, 3b and 3c which were further synthesized and subjected to in vivo hypoglycemic, total cholesterol (CHL) and triglyceride (TG) evaluation. 14 days treatment revealed significant reduction in blood glucose levels but did not portray desirable results in terms of total CHL and TG lowering effect. The blood glucose reduction observed for 3a, 3b and 3c at 20 mg/kg/day was 53.96 %, 61.35%, 61.32% respectively as against 59.95% of the standard pioglitazone at 10mg/kg/day.

The objective of the present study was to develop superparamagnetic chitosan(CS) - dextran sulfate(DS) hydrogels as a intelligent drug system for effective carrying of Chlorin E6(chn E6) photosensitizer to cancer cells. This system can be detectable by magnetic Resonance Imaging technique. The study shows that the lifetime of the triplet state for chn E6 photosensitizer is significantly increase when encapsulate into hydrogel. In addition to the possible enhancement of 1O2 generation, other advantages to incorporating chn E6 -based PS agents into hydrogel include the ability to solubilize these generally hydrophobic agents, the small and uniform size of hydrogels, and potential for passive targeting of solid tumors via the enhanced permeation and retention effect decreasing systemic photosensitization.

Synthesis and biological evaluation of a novel series of substituted pentacyclic triterpene derivatives as potential PPARγ agoinsts and glycogen phosphorylase inhibitors have been described. Compounds 11 and 17 showed potent PPARγ agonistic activity and activated the transcription activity of PPARγ in a dose-dependent manner. On the other hand, eleven compounds exhibited moderate inhibitory activity against rabbit muscle glycogen phosphorylase a (RMGPa), and triterpene 10 was the best one. Structure-activity relationship (SAR) is also discussed.

Histone deacetylases (HDACs) belong to a superfamily of enzymes responsible for deacetylating the Nterminal tails of histones. Overproduction of HDACs has a significant role in tumorigenesis. Accordingly, inhibition of HDACs has been widely applied for cancer therapy. It is encouraging that some natural products showed promising potency and selectivity against HDACs. In order to uncover their keys of good performance, the binding patterns of several natural HDAC1 inhibitors in the active site of HDAC1 were navigated by homology modeling, docking and molecular dynamic simulations. Evaluation of the binding poses allowed us to recognize the roles of different residues around the active site, and to understand the core features in the structure of the inhibitor molecule. Hydrophobic and H-bond interactions formed between the ligand and residues were discovered to make significant contributions to the ligand-receptor binding. Finally, the structural requirement of inhibitors for binding to HDAC1 was well proposed. Our results are beneficial to the design of potent HDAC1 inhibitors.

Because of the importance of proteins in inducing allergenic reactions, the ability of predicting their potential allergenicity has become an important issue. Bioinformatics presents valuable tools for analyzing allergens and these complementary approaches can help traditional techniques to study allergens. This work proposes a computational method for predicting the allergenic proteins. The prediction was performed using pseudo-amino acid composition (PseAAC) and Support Vector Machines (SVMs). The predictor efficiency was evaluated by fivefold cross-validation. The overall prediction accuracies and Matthew’s correlation coefficient (MCC) obtained by this method were 91.19% and 0.82, respectively. Furthermore, the minimum Redundancy and Maximum Relevance (mRMR) feature selection method was utilized for measuring the effect and power of each feature. Interestingly, in our study all six characters (hydrophobicity, hydrophilicity, side chain mass, pK1, pK2 and pI) are present among the 10 higher ranked features obtained from the mRMR feature selection method.

In the present molecular modelling study, recently discovered 36 selective urea derivatives were considered to develop pharmacophore based 3D-QSAR model coupled with quantum mechanics (QM) calculations to uncover the essential structural features of urea molecules for mPGES-1 inhibition. The 3D-QSAR model was selected on the basis of highest values of external predictability parameters i.e. Q2 (0.775) and Pearson-r (0.912). The model also showed the highest values of R2, 0.985; F-value, 306.3 and least SD, 0.147. The selected model was further validated for its external prediction power by calculating k, k´ , R2 o and R´2 o. The contour maps generated against the selected QSAR model helped to interpret the important molecular sites of urea derivatives where the suitable structural modifications would help in better complementary fit to the active site of mPGES-1, in turn would improve the potency of newly designed molecules.

Dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A) is a protein kinase with diverse functions in neuronal development and adult brain physiology. Elevated levels of Dyrk1A are associated with the pathology of neurodegenerative diseases and have been implicated in some neurobiological alterations of Down syndrome, such as mental retardation. Meridianins are marine derived indole alkaloids exhibiting anti-proliferative activity as well as are known to inhibit panel of kinases. In the present article, a descriptor based QSAR study was carried out for a series of meridianin analogs inhibiting Dyrk1A to find out structural features which are crucial for biological activity. Developed QSAR model showed good correlation coefficient (r > 0.9), higher F value (F > 20) and excellent predictive power (r2 cv and r2 pred > 0.6). Activity of naturally occurring meridianins was also predicted using developed model. The study indicated that kier Chi4 path/cluster, total lipole, VAMP polarization ZZ component, dipole moment Z component and log P plays important role in Dyrk1A inhibition. Further analysis of pharmacophore model using PHASE module of Schrodinger revealed that two hydrogen bond acceptors (A), two hydrogen bond donors (D) and two hydrophobic aromatic rings (R) are crucial molecular features that predict binding affinity for meridianins to the Dyrk1A enzyme. These observations provide important insights to the key structural requirements of meridianins for potent Dyrk1A inhibition. Excellent statistical results of developed models strongly suggest that these models are reasonable for prediction of the activity of new inhibitors and in future drug design.