Open Medicinal Chemistry Journal最新文献

Protozoan parasites cause serious human and zoonotic infections, including life-threatening diseases such as malaria, African and American trypanosomiasis, and leishmaniasis. These diseases are no more common in the developed world, but together they still threaten about 40% of the world population (WHO estimates). Mortality and morbidity are high in developing countries, and the lack of vaccines makes chemotherapy the only suitable option. However, available antiparasitic drugs are hampered by more or less marked toxic side effects and by the emergence of drug resistance. As the main prevalence of parasitic diseases occurs in the poorest areas of the world, the interest of the pharmaceutical companies in the development of new drugs has been traditionally scarce. The establishment of public-private partnerships focused on tropical diseases is changing this situation, allowing the exploitation of the technological advances that took place during the past decade related to genomics, proteomics, and in silico drug discovery approaches. These techniques allowed the identification of new molecular targets that in some cases are shared by different parasites. In this review we outline the recent developments in the fields of protease and topoisomerase inhibitors, antimicrobial and cell-penetrating peptides, and RNA interference. We also report on the rapidly developing field of new vectors (micro and nano particles, mesoporous materials) that in some cases can cross host or parasite natural barriers and, by selectively delivering new or already in use drugs to the target site, minimize dosage and side effects.

The impact of highly active antiretroviral therapy (HAART) in the natural history of AIDS disease has been allowed to prolong the survival of people with HIV infection, particularly whose with increased HIV viral load. Additionally, the antiretroviral therapy could exert a certain degree of protection against parasitic diseases. A number of studies have been evidenced a decrease in the incidence of opportunistic parasitic infections in the era of HAART. Although these changes have been attributed to the restoration of cell-mediated immunity, induced by either non-nucleoside reverse transcriptase inhibitors or HIV protease inhibitors, in combination with at least two nucleoside reverse transcriptase inhibitors included in HAART, there are evidence that the control of these parasitic infections in HIV-positive persons under HAART, is also induced by the inhibition of the proteases of the parasites. This review focuses on the principal available data related with therapeutic HIV-protease inhibitors and their in vitro and in vivo effects on the opportunistic protozoan parasites.

Investigation of in vitro hydroxyl radical scavenging (antioxidant) effect 4-methoxychalcone (1a) and its cyclic analogues (2a-4a), as well as their hydroxyl substituted counterparts (1b-4b) was performed by means of the Fenton-reaction initiated deoxyribose degradation assay in short term (10 minute) and long term (240 minute) experiments. The kinetic deoxyribose method provides possibility to investigate not only the short term antioxidant (hydroxyl radical scavenger) effect but the possible late prooxidant effect of the tested substances as well. In the short term studies compounds 2a, 2b and 4b showed the most pronounced antioxidant effect. The long-term studies showed that the antioxidant activity of all the tested compounds but 4a can be well characterized by the short time determination of the thiobarbituric acid (TBA)-reactive substances (TBARS). Experiments in the presence of ethylenediaminetetraacetic acid (EDTA) resulted in a substantially reduced degradation of deoxyribose in each incubation. Similar to the respective experiment performed without EDTA, the TBARS level of the incubations with 4a showed an increase over the 60-120 minute period. The results demonstrated that complex forming activities that can modify microspeciation and reactivity of iron ions can lead to different short term antioxidant efficiency of the tested substances. Results of the long term incubations indicated that chemical transformation of the tested substances can result formation of derivatives that can initiate further redox activities under the experimental conditions.

The diseases caused by protozoan parasite are responsible for considerable mortality and morbidity, affecting more than 500 million of people in the world. The epidemiological control of protozoan is unsatisfactory due to difficulties of vector and reservoir control; while the progress in the development of vaccine tends to be slow and arduous. Currently, the chemotherapy remains essential component of both clinical management and disease control programmer in endemic areas. The drugs in use as anti-protozoan agents were discovered over 50 years and a number of factors limit their utility such as: high cost, poor compliance, drug resistance, low efficacy and poor safety. In the recent years, the searches about the development of new drugs against protozoa parasite have been increased. This special issue of The Open Medicinal Chemistry Journal will present some of developments in this field with the aim to shown the significant advances in the discovery of new anti-protozoan drugs.

Recent years have seen a significant improvement in available treatment options for leishmaniasis. Two new drugs, miltefosine and paromomycin, have been registered for the treatment of visceral leishmaniasis (VL) in India since 2002. Combination therapy is now explored in clinical trials as a new treatment approach for VL to reduce the length of treatment and potentially prevent selection of resistant parasites. However there is still a need for new drugs due to safety, resistance, stability and cost issues with existing therapies. The search for topical treatments for cutaneous leishmaniasis (CL) is ongoing. This review gives a brief overview of recent developments and approaches in anti-leishmanial drug discovery and development.

Regulation of the SLC12 family of membrane transporters including NCCT involves a scaffold of interacting proteins including the STE 20 kinase SPAK and the WNK kinases, WNK 1 and WNK 4, which are mutated in the hypertensive syndrome of pseudohypoaldosteronism type 2 (PHAII). WNK4 regulates NCCT by affecting forward trafficking to the surface membrane. Studies in Xenopus using kinase dead WNK4 site mutants have produced inconsistent results with regard to the necessity of kinase function for NCCT regulation. Dynamic inhibition of WNK4 by small molecules may bring clarity to this issue however WNK4 is naturally resistant to commercial MAP kinase inhibitors owing to steric constraints prohibiting entry of small molecules to the active site. Using an approach similar to that used in p38 and ERK, we show that a single substitution in WNK4 (T261G) dramatically enhances its susceptibility to the inhibitors SB 202190 and SB 203580.

Accumulating evidence suggests that α7 nicotinic receptors (α7 nAChRs), a subtype of nAChRs, play a role in the pathophysiology of neuropsychiatric diseases, including schizophrenia and Alzheimer's disease (AD). A number of psychopharmacological and genetic studies shown that α7 nAChRs play an important role in the deficits of P50 auditory evoked potential in patients with schizophrenia, and that (α nAChR agonists would be potential therapeutic drugs for cognitive impairments associated with P50 deficits in schizophrenia. Furthermore, some studies have demonstrated that α7 nAChRs might play a key role in the amyloid-β (Aβ)-mediated pathology of AD, and that α7 nAChR agonists would be potential therapeutic drugs for Aβ deposition in the brains of patients with AD. Interestingly, the altered expression of α7 nAChRs in the postmortem brain tissues from patients with schizophrenia and AD has been reported. Based on all these findings, selective α7 nAChR agonists can be considered potential therapeutic drugs for cognitive impairments in both schizophrenia and AD. In this article, we review the recent research into the role of α7 nAChRs in the pathophysiology of these diseases and into the potential use of novel α7 nAChR agonists as therapeutic drugs.

Metabotropic glutamate receptors (mGlu receptors) have emerged as new therapeutic targets for psychiatric disorders, such as schizophrenia, depression and anxiety with their regulatory roles in glutamatergic transmissions. To date, several ligands selective for each mGlu receptor have been synthesized, and pharmacological significances of these ligands have been demonstrated in animal models. Among them, mGlu2/3 receptor agonists have been proven to be effective for treating schizophrenia and anxiety disorders in clinical studies, which may prove utilities of mGlu receptor ligands for the treatment of psychiatric disorders. This article reviews recent advances in development of each mGlu receptor ligands and their therapeutic potential.

D-amino acid oxidase (DAAO) is a flavoenzyme that degrades D-amino acids through the process of oxidative deamination. DAAO regulation of D-amino acid levels has been associated with several physiological processes ranging from hormone secretion to synaptic transmission and cognition. Recent genetic studies have identified a mutation on chromosome 13 in schizophrenia patients that encodes two gene products (G30 and G72) that are associated with DAAO. Furthermore, DAAO expression and enzyme activity has been reported to be increased in post mortem brain tissue samples from patients with schizophrenia compared to healthy controls. D-serine, a D-amino acid that is regulated by DAAO, is a potent, endogenous co-agonist of the N-methyl-D-aspartic acid (NMDA) receptor. Because NMDA receptor dysfunction is thought to be involved in the positive (psychotic), negative and cognitive symptoms in schizophrenia, there has been much interest in developing potent and selective DAAO inhibitors for the treatment of this disease. Several research reports have been published that describe the synthesis and biological effects of novel, selective, small molecule inhibitors of DAAO. Many of these compounds have been shown, when given systemically, to increase D-serine concentrations in the blood and brain. However, the efficacy of these compounds in behavioral assays that measure antipsychotic potential and pro-cognitive effects in laboratory animals has been inconsistent. This article highlights and reviews research advances for DAAO inhibitors published in peer reviewed journals.