Medicinal Chemistry

Fixed-dose combination chemotherapy holds great potential for management of cancer. Thus a drug delivery system which can administer a controlled ratio of several drugs simultaneously and control the drug release at the cancer site is highly desired. In this work, a fixed-dose dual drug loaded polymer micelle is formed by the self-assembly of a single polymer–drug conjugate carrying a combination of drugs. A predetermined ratio of the two drugs can be obtained via a facile and efficient solid-phase synthesis method. MTT assay demonstrated that the polymer micelles are more effective in altering the proliferation rate of MCF-7 tumor cells due to its higher solubility than free drugs. Furthermore, the introduction of the redox-sensitive disulfide linker between the hydrophilic PEG and the hydrophobic drugs facilitates drug release in tumor cellular redox environment and thus enhances the therapeutic effectiveness dramatically.

‘Diabetic dyslipidemia’ (combination of raised triglyceride levels, raised small-dense Low-density lipoprotein particles and low high-density lipoprotein cholesterol levels) is the most prominent risk factor of atherosclerosis and cardiovascular disease. Despite statin therapy and LDL-lowering, a high residual risk of cardiovascular events persists. High triglyceride levels and low high-density lipoprotein cholesterol levels singly and collectively increase the risk of cardiovascular events in type 2 diabetes mellitus and guidelines recommend modifying these secondary therapeutic targets to provide additional vascular protection.Addition of a fibrate or niacinareoptions for combination with a statin to reduce atherogenic dyslipidemia and are clearly effective at raising high-density lipoprotein cholesterol levels and lowering triglycerides.Addition of high dose omega-3 fatty acids (2-3 gm/day) with a statin are also effective in lowering triglyceride, but their effects on cardiovascular events remain uncertain and are complicated with safety issues. Saroglitazar is a novel dual Peroxisome Proliferator-Activated Receptors-α/γ agonist and the first glitazar approved in the world for the treatment of diabetic dyslipidemia by Drug Controller General of India in June 2013. Saroglitazar (2 mg and 4 mg) therapy has shown significant (45%) reduction in triglycerides, significant reduction of other atherogenic lipids (Low-density lipoprotein, very-low density lipoprotein, total cholesterol and apolipoprotein-B) and significant improvement of glycemic status, with relatively free from side effects. It has emerged with a hope to further reduce the incidence of cardiovascular disease among statin treated diabetic subjects. However, the trial populations were small and toxicity data may emerge with increasing use of this drug. Moreover, in absence of outcome studies and large multi-center longitudinal follow up data, the clinical cardiovascular efficacy is uncertain till date.

Functionalized acridines, tetrahydroacridines and quinolines were evaluated for in vitro AChE and BChE inhibitory activities. Potent nanomolar inhibition of both enzymes was found in the tacrine-donepezil hybrid N-(1-benzylpiperidin- 4-yl)-6-chloro-1,2,3,4-tetrahydroacridin-9-amine (51). Molecular modelling and kinetic studies support the notion that 51 occupied the catalytic and peripheral anionic sites of AChE. The physicochemical properties (polar surface area, lipophilicity, hydrogen bonding characteristics) of 51 were within the threshold limits for permeability across the blood brain barrier. Thus, 51 is a promising hybrid inhibitor derived from two established with clinical relevance to neurodegenerative diseases.

Clonorchiasis is a common infection of dogs and other fish-eating carnivores (reservoir final hosts). Praziquantel is the only medicine, which has been recommended by WHO for treatment of clonorchiasis. To investigate the interaction between praziquantel and Clonorchiasis sinensis cercariae, two praziquantel derivatives (PZQ-2 and PZQ-3) and one praziquantel fluorescent derivative (PZQ-5) were have been synthesized and characterized by nuclear magnetic resonance spectroscopy (NMR) and MS spectra. Confocal fluorescence microscopy revealed that PZQ-5 is mainly located at cercarial tegument, which leads to the death of cercariae with the time increasing.

Alzheimer’s disease (AD) is one of the neurodegenerative diseases that affect millions of people worldwide. AD could rob patients of their ability to recall, reason and carry out executive functions. Pathophysiological studies of AD have revealed the gradual loss of neurons, function and ultimate death of neurons (apoptosis). Mutations, oxidative stress, excitotoxicity, infectious diseases are among the principal causes of neuronal degeneration. Despite the prescription of a wide range of drugs to treat AD, the emergence of effective treatments to halt the progress or reverse this disease has remained elusive for years. Series of preclinical studies have been developed to ensure better understanding of the neurobiology of AD and engender the discovery of new drugs. This review provides an overview on the pathophysiology, pharmacotherapy and preclinical models of AD in an attempt to bring together current research efforts, challenges, achievements and prospect for the discovery of drugs to treat AD. Pathophysiological evidences of this neurodegenerative disease has shown the involvement of multiple neural mechanisms. So far, the research approaches and treatment of this disease still remain largely unsatisfactory. However, there are possibilities of surmounting current challenges with new technology, diagnostic criteria and translational approach that effectively reflect clinical etiology of AD in experimental animals.

The current manuscript describes the design, synthesis, and in vitro testing of four thioacetanilides with diltiazemverapamil hybrid structural features as potential calcium channel blockers. The current hybrid strategy of drug design aimed to generate compounds that could span, with a single compound, the trans-membrane locales where the two drugs bind, with the ultimate goal of increasing the blocking activity. The latter, was assessed by measuring the inhibitory effects, expressed as IC50, on calcium-induced contractions of potassium depolarized isolated rat aorta strips. The assessment of the binding locales was determined by incubating the test compound with aortic strips for two different periods, 10-minutes and 2-hours, before adding the contractile calcium ions to the assay medium. Diltiazem IC50 values were 0.26 and 0.14 μM, after 10-minutes and 2-hours, respectively, reflecting less than two fold increase in activity and confirming previous reports that its locale of binding in mostly on the exterior side of the membrane. On the other hand, verapamil IC50 values were 0.47 and 0.14 μM after 10-minutes and 2-hour incubation respectively, reflecting approximately a 3-4 fold increase in activity and confirming previous reports that it binds mainly to the interior domains of the membrane. The four designed hybrid compounds showed, after 10-minute incubation, an IC50 value range of 3.7-12.0 μM, and after 2-hour incubation an IC50 range of 0.78-2.12 μM, reflecting approximately a 5-fold increase in activity suggesting more similarity to the verapamil binding profile. The data indicate that the designed compounds are with moderate activities, but generally less active as calcium channel blockers than either of the two parent drugs.

The natural product sterol 5α,8α-endoperoxides are structural different from general sterols. These compounds belong to the group of oxidized sterol derivatives and contain a 5α,8α-endoperoxide bond in addition to the fragments characteristic of original sterols. Many researches have reported that sterol 5α,8α-endoperoxides have potential bioactivities, including antioxidant, antimicrobial, anti-tumor activity, immunomodulatory activity, inhibitory hemolytic activity and anti-inflammatory activity etc. The review discussed the structures, properties, bioactivity and synthetic methods of sterol 5α,8α-endoperoxides. The natural peroxides are valuable sources in the development of novel bioactive agents.

Aim and objectives: Herbal drugs such as, Capparis Spinosa (CS) has been used to treat several diseases from heart and cardiovascular disorders to diabetes in traditional Iranian medicine. The present study was aimed to determine beneficiary effects of CS fruit extract on a number of tissues in healthy and type 1 diabetic rat.
Materials and methods: In this experimental study, sixty male wistar rats were randomly divided into 6 groups (n=10) and subjected to gavage tube therapy for one months by following protocol: group I and IV: diabetic control and non-diabetic control rats which only received distilled water; groups II and III: non diabetic treatment rats which received 200 mg/kg and 800 mg/kg CS extract per day respectively; groups V and VI: diabetic treatment rats which received 200 mg/kg and 800 mg/kg CS extract per day respectively. Diabetes was induced by intra-peritoneal injection of 50 mg/kg of streptozotocin (STZ). After 4 weeks, their blood were collected and the serum levels of creatinine, bilirubin, urea, uric acid, AST, ALT and ALP were measured. The liver, kidney, pancreas and stomach tissues were immediately excised, and after slide preparation processes, the histological changes were studied.
Results: Our results illustrated that the gastric tissue in the diabetic group showed a small degree of changes and was not affected significantly by administration of the CS fruit extract. Liver, pancreas and kidney of diabetic rats exhibited considerable changes, like cellular necrosis. These changes in diabetic treatment groups were at lowest amounts. The decrease levels of creatinine, liver enzymes, and other factors were supporting these changes.
Conclusions: This study demonstrates that the CS fruit extract could be aid prevention of damage to the tissues due to the decreased levels of harmful oxidants in the body in diabetes. Moreover, according to our previous results altogether we showed beneficial impact of the plant on the treatment of diabetes.