Medicinal Chemistry - Volume 3, Issue 4, 2007

Malaria, the most important of the human parasitic diseases, causes about 500 million infections worldwide and over 1 million deaths every year. The search for novel drug candidates against specific parasitic targets is an important goal for antimalarial drug discovery. Recently the antimalarial activity of chalcones has generated great interest. These compounds are small non-chiral molecules with relative high lipophilicity (clogP ∼ 5-7), have molecular weights in the range of 300 to 600 g/mol, and possess in vivo efficacy against both P. berghei and P. yeolii. Preliminary data on our ongoing chalcone synthesis project indicate that these compounds are active in vitro against P. falciparum, but are rapidly metabolized in liver microsome assays. Structurally-related compounds not including the enone linker are found to be much more metabolically stable and yet have comparable in vitro efficacy. In this study, we have utilized the efficacy data from an in-house on-going chalcone project to develop a 3D pharmacophore for antimalarial activity and used it to conduct virtual screening (in silico search) of a chemical library which resulted in identification of several potent chalconelike antimalarials. The pharmacophore is found to contain an aromatic and an aliphatic hydrophobic site, one hydrogen bond donor site, and a ring aromatic feature distributed over a 3D space. The identified compounds were not only found to be potent in vitro against several drug resistant and susceptible strains of P. falciparum and have better metabolic stability, but included one with good in vivo efficacy in a mouse model of malaria.

Our interest has been centered on flavonol glycosides from Croton Menthodorus (Euphorbiaceae) and Aristeguietia discolor (Asteraceae). In this respect, the effect of flavonol glycosides from Croton Menthodorus (Euphorbiaceae) and Aristeguietia discolor (Asteraceae) was investigated on the naloxone-precipitated withdrawal contracture of the acute morphine-dependent guinea-pig ileum in vitro. Furthermore, the effect of these flavonol glycosides was also considered on DAGO (highly selective μ-agonist) and U50-488H (highly selective k-agonist) withdrawal to test whether the possible interaction of flavonol glycosides on opioid withdrawal involves μ- and/or k-opioid receptors. Flavonol glycosides from Croton Menthodorus (1x10-5 , 5x10-5 and 1x10-4 M) and from Aristeguietia discolor (1x10-7-1x10-6-1x10-5 M) before or after the opioid agonists were able to both prevent and reverse the naloxone-induced contracture after exposure to μ (morphine and DAGO) or k (U50-488H) opiate agonists in a concentration-dependent fascion. Both acetylcholine response and electrical stimulation were reduced by flavonol glycosides treatment as well as the final opiate withdrawal was still reduced. The results of the present study indicate that flavonol glycosides were able to produce significant influence on the opiate withdrawal in vitro and these compounds were able to exert their effects both at μ and k opioid agonists.

Botulinum toxin is used as first line therapy for some muscular disorders, and is efficacious in treating hypersecretory and some pain syndromes. When used appropriately it has a good safety profile. It has been evaluated in treating a number of conditions that as yet do not have obvious effective or beneficial treatment. With the greater acceptance and use of botulinum toxin therapy for cosmetic purposes, botulinum toxin use will increase. An understanding of the pharmacology, and potential adverse effects is essential for the physician when managing patients having or who would benefit from botulinum toxin therapy.

Quantification of structure activity relationships was performed on a series of indazole estrogen analogs, for their relative β estrogenic receptor agonist activity, in order to understand the essential structural requirements for selectivity of indazole estrogen analogs for β-estrogenic receptor over α-estrogenic receptor. The de novo and Hansch approach suggested that the 3rd position of indazole nucleus (R1) is decisive for the selectivity of molecules towards β- estrogenic receptor over β-estrogenic receptor. The study also depicted that the substitution of polar group at R1 position might prove helpful in the β-estrogenic receptor selectivity (ERβ/α).

A series of 1,3-thiazolidin-4-ones and metathiazanones were synthesized and evaluated as anti-HIV agents. The results of the in vitro assays showed that some of the synthesized compounds were effective inhibitor of reverse transcriptase enzyme of human immunodeficiency virus type-1 (HIV-1) at micromolar concentrations with less cytotoxicity in MT-4 cells as compared to thiazolobenzimidazole (TBZ). Structure-activity relationship studies revealed that the nature of the substituents at the 2 and 3 positions of the thiazolidin-4-one nucleus had a significant impact on the in vitro anti-HIV activity of this class of antiretroviral agents. One of the compounds, 1, inhibited the enzyme at 0.204μM concentrations with minimal cytotoxicity to MT-4 cells.

Recently, there has been great progress in elucidating the biochemistry of the arachidonic acid (AA) metabolism. The abnormal production of leukotrienes (LTs), due to the unbalanced-regulation of synthesizing and catabolizing enzymes, is probably induced by many bioactive substances, including Th2 cell-derived cytokines. Imbalances in these processes may play an important role in allergic reactions and other inflammatory diseases, thus making them potentially prime therapeutic targets for these diseases. Further studies on the regulation of LT-synthesis and catabolism are therefore required to clarify the importance of these imbalances on the initiation and progression of allergic and inflammatory diseases.

Cancer is a serious worldwide health threat, killing almost seven million people per year. Quinones are an important class of antitumour agents that are activated by tumour hypoxia. Primin (2-methoxy-6-n-pentyl-1,4-benzoquinone), a naturally-occurring product obtained from Primula obconica (Primulaceae) has shown antimicrobial and antitumour properties. The synthesis of the Primin to obtain 3-, 5- or 6-alkyl substituted derivatives has been previously attempted seeking antitumour activity. The intermediate reaction products, 2-methoxy-hydroquinone-di-(2'-tetrahydropyranyl) ether and 2-methoxy-6-n-pentyl-hydroquinone-di-(2'-tetrahydropyranyl) ether were obtained and evaluated against sarcoma 180 (S-180) and Ehrlich carcinoma, as well as toxicity tests were performed. The antitumour activity tests showed that these intermediate compounds were able to inhibit S-180 sarcoma and Ehrlich carcinoma growth in mice. These results indicated that the tetrahydropyranyl protect group conserved the antitumour activity in comparison with quinone group, however, it exhibited a less toxic effect, with no characteristic of quinones. These results can suggest that compound 2-methoxy-6-n-pentyl-hydroquinone-di-(2'-tetrahydropyranyl) ether may act as a prodrug with some advantages in comparison with the Primin.

A series of all-trans-1-aryl-4-aryl-5-aryl-2,4-pentanediene-1-one (3), a hybridized form of chalcone and combretastatin, was synthesized and evaluated against a panel of cancer cell lines, including B16, murine melanoma; HCT116, colon cancer; A431, human epidermoid carcinoma; and human umbilical venous endothelial cells (HUVEC). Structure-activity relationships analysis of this series revealed that a 2,5-dihydroxyphenyl at position 1 of the 2,4- pentanediene-1-one was essential for cytotoxicity. all-trans-1-(2,5-Dihydroxyphenyl)-5-(4-methoxyphenyl)-4-(3,4,5- trimethoxyphenyl)-2,4-pentanediene-1-one (3a) was the most potent compound from this series.

Selective inhibition of Ciliary process enzyme i.e. Carbonic Anhydrase-II is an excellent approach in reducing elevated intraocular pressure, thus treating glaucoma. Due to characteristic physicochemical properties of sulphonamide (Inhibition of Carbonic Anhydrase), they are clinically effective against glaucoma. But the non-specificity of sulphonamide derivatives to isozyme, leads to a range of side effects. Presently, the absence of comparative studies related to the binding of the sulphonamides as inhibitors to CA isozymes limits their use. In this paper we have represented “Three Dimensional Quantitative Structure Activity Relationship” study to characterize structural features of Sulfamide derivative [RR'NSO2NH2] as inhibitors, that are required for selective binding of carbonic anhydrase isozymes (CAI and CAII). In the analysis, stepwise multiple linear regression was performed using physiochemical parameters as independent variable and CA-I and CA-II inhibitory activity as dependent variable, respectively. The best multiparametric QSAR model obtained for CA-I inhibitory activity shows good statistical significance (r= 0.9714) and predictability (Q2=0.8921), involving the Electronic descriptors viz. Highest Occupied Molecular Orbital, Lowest Unoccupied Molecular Orbital and Steric descriptors viz. Principal moment of Inertia at X axis. Similarly, CA-II inhibitory activity also shows good statistical significance (r=0.9644) and predictability (Q2=0.8699) involving aforementioned descriptors. The predictive power of the model was successfully tested externally using a set of six compounds as test set for CA-I inhibitory activity and a set of seven compounds in case of CA-II inhibitory activity with good predictive squared correlation coefficient, r2 pred=0.6016 and 0.7662, respectively. Overview of analysis favours substituents with high electronegativity and less bulk at R and R' positions of the parent nucleus, provides a basis to design new Sulfamide derivatives possessing potent and selective carbonic anhydrase-II inhibitory activity.

Despite accumulating evidence showing that TNF-related apoptosis inducing ligand (TRAIL) plays a role in vascular biology and that its decoy receptor osteoprotegerin (OPG) is expressed in the vessel wall, modulation of these TNF and TNF-R family members in the early phases of diabetes mellitus has not been investigated. The expression of TRAIL and of OPG was examined both at the mRNA and protein levels in control and streptozotocin (SZT)-induced diabetic rats at early time points after the induction of diabetes mellitus. No differences in the steady-state mRNA levels of TRAIL were noticed by quantitative RT-PCR among the two groups of animals. On the other hand, diabetic rats showed a rapid and significant increase of the steady-state mRNA levels of OPG in the aortic wall of diabetic animals with respect to vehicle-treated (control) animals. These findings were confirmed at the protein level by analysing the amount of TRAIL and OPG proteins in aortic lysates by either Western blot or immunohistochemistry. Thus, an abnormal elevation of the OPG/TRAIL ratio in the vessel wall characterizes the early onset of diabetes mellitus and might represent a molecular mechanism involved in the vascular dysfunction characterizing diabetes mellitus.

The enzyme GSK-3 plays a central role in cells during the phosphorylation of various key regulatory proteins, and consequently pharmacological inhibitors of this enzyme potentially allow the treatment of diseases that include neurodegenerative and bipolar affective disorders, diabetes, and diseases caused by unicellular parasites. Today there is a huge number of reported empirical structure-activity relationships (SAR) that may guide a rational design of more potent and selective inhibitors. However, only a few studies based on Quantitative Structure-Activity Relationships (QSAR) are available for predicting the inhibitor potency against this specific kinase, and they involve mainly molecular modeling and 3D-QSAR. The present review deals with the recent search for a quantitative analysis of GSK-3 inhibition.