SYNTHESIS AND ANTIPLASMODIAL ACTIVITY OF SOME NOVEL CHALCONE DERIVATIVES

Increased drug resistance in malaria toward many of the existing antimalarials make the condition worse. Hence, indicates the necessity of thenovel molecules to overcome the problem. A series of chalcone derivatives (3a-4e) were primed via Claisen-Schmidt condensation of substitutedaldehydes with substituted methyl ketones. These derivatives were tested against Plasmodium falciparum clinical isolate for their antiplasmodialactivity. Furthermore, in-vitro β-hematin formation assay has been conducted in order to gain insight into the possible mechanism of action. Outof the 10 synthesized compounds, two compounds 4a and 4d exhibited promising antiplasmodial activities (50% inhibitory concentration [IC50]values 7.45±0.65 and 6.01±0.29 μg/ml, respectively). Other compounds (3a, 4b, 4e and 3d) showed moderate inhibition against P. falciparum. Amongall the compounds, 4a showed good hemozoin inhibitory activity (IC50 - 19.75 μg/ml) while 3a and 4d showed moderate type inhibition. Thesemolecules may act as templates for medicinal chemistry to discover novel and hybrid molecules with improved characteristics, which may becomefuture candidates for the treatment of malaria.Keywords: Chalcone, Malaria, Plasmodium falciparum, β-hematin.Â

Na+, K+-ATPase Signaling and Bipolar Disorder

Bipolar disorder (BD) is a severe and common chronic mental illness characterized by recurrent mood swings between depression and mania. The biological basis of the disease is poorly understood and its treatment is unsatisfactory. Although in past decades the “monoamine hypothesis” has dominated our understanding of both the pathophysiology of depressive disorders and the action of pharmacological treatments, recent studies focus on the involvement of additional neurotransmitters/neuromodulators systems and cellular processes in BD. Here, evidence for the participation of Na+, K+-ATPase and its endogenous regulators, the endogenous cardiac steroids (ECS), in the etiology of BD is reviewed. Proof for the involvement of brain Na+, K+-ATPase and ECS in behavior is summarized and it is hypothesized that ECS-Na+, K+-ATPase-induced activation of intracellular signaling participates in the mechanisms underlying BD. We propose that the activation of ERK, AKT, and NFκB, resulting from ECS-Na+, K+-ATPase interaction, modifies neuronal activity and neurotransmission which, in turn, participate in the regulation of behavior and BD. These observations suggest Na+, K+-ATPase-mediated signaling is a potential target for drug development for the treatment of BD

Na+, K+-ATPase α Isoforms and Endogenous Cardiac Steroids in Prefrontal Cortex of Bipolar Patients and Controls

Bipolar disorder is a chronic multifactorial psychiatric illness that affects the mood, cognition, and functioning of about 1–2% of the world’s population. Its biological basis is unknown, and its treatment is unsatisfactory. The α1, α2, and α3 isoforms of the Na+, K+-ATPase, an essential membrane transporter, are vital for neuronal and glial function. The enzyme and its regulators, endogenous cardiac steroids like ouabain and marinobufagenin, are implicated in neuropsychiatric disorders, bipolar disorder in particular. Here, we address the hypothesis that the α isoforms of the Na+, K+-ATPase and its regulators are altered in the prefrontal cortex of bipolar disease patients. The α isoforms were determined by Western blot and ouabain and marinobufagenin by specific and sensitive immunoassays. We found that the α2 and α3 isoforms were significantly higher and marinobufagenin levels were significantly lower in the prefrontal cortex of the bipolar disease patients compared with those in the control. A positive correlation was found between the levels of the three α isoforms in all samples and between the α1 isoform and ouabain levels in the controls. These results are in accordance with the notion that the Na+, K+-ATPase-endogenous cardiac steroids system is involved in bipolar disease and suggest that it may be used as a target for drug development

Synthesis and Biological Evaluation of Novel Bufalin Derivatives

Bufalin and other cardiac steroids (CS) have been used for centuries for the treatment of congestive heart failure, arrhythmias, and other maladies. However, toxicity and the small therapeutic window of this family of steroids limit their use. Therefore, attempts to synthesize a potent, but less toxic, CS are of major importance. In the present study, two novel bufalin derivatives were synthesized and some of their pharmacological properties were characterized. The reaction of bufalin with Ishikawa’s reagent resulted in the production of two novel bufalin derivatives: bufalin 2,3-ene and bufalin 3,4-ene. The compounds were purified with TLC and HPLC and their structure was verified with UV, NMR, and MS analyses. The biological activities of these compounds were evaluated by testing their ability to inhibit the Na+, K+-ATPase activity of the brain microsomal fraction to induce cytotoxic activity against the NCI-60 human tumor cell line panel and non-cancer human cells, and to increase the force of contraction of quail embryonic heart muscle cells in culture. The two steroids exhibited biological activities similar to those of other CS in the tested experimental systems, but with reduced cytotoxicity, advocating their development as drugs for the treatment of heart failure and arrhythmias