Mini Reviews in Medicinal Chemistry - Volume 18, Issue 1, 2018

At present there are about 47.5 million people having different types of dementia and by 2030 this number would reach 75.6 million. This obviously brings about a serious social and economic burden for people who take care for those with any kind of dementia. The purpose of this article is to explore only semantic dementia (SD), more specifically called semantic variant of primary progressive aphasia, as one of the forms of frontotemporal dementia (FTD) and provide the latest information on its diagnosis and treatment which play a significant role in the maintenance of quality of life of both patients and their caregivers. Especially unimpaired communication is one of the key factors in the relationship between the patients and their caregivers. The methods used for this mini review include a literature review of available sources found in the world’s acknowledged databases such as Web of Science, PubMed, Springer and Scopus from 2000 to 2015; and a comparison and evaluation of the selected studies. The findings of this mini review show that FTD, respectively SD, is a serious neurodegenerative disorder which has fatal consequences for the affected patients. In addition, the findings also indicate that there are not many possibilities of pharmacological treatment for semantic dementia and therefore more attention should be paid to alternative, non-pharmacological approaches. Although semantic dementia is a relatively rare neurodegenerative disorder if compared with other types of dementia, it has an irreversible impact on patient’s and his/her caregiver's life in terms of quality.

The indole scaffold is found in a wide range of bioactive heterocycles and natural products. Moreover, the indole moiety is considered as the active principle in several alkaloids such as mitomycin C and reserpine. Thus, over the past decade, chemists are increasingly attracted towards the studies on the pharmacological and therapeutic activities of indole containing compounds. Furthermore, the molecular structures of well-known drugs such as sumatriptan, tadalafil, fluvastatin and rizatriptan are based on indole frameworks. This mini-review covers some of the significant and recent achievements of indole derivatives with respect to their biological activities up to 2015.

Soon after the identification of Leishmania parasite as a causative agent, the pentavalent antimony compounds have been the mainstay to treat all forms of leishmaniasis. Due to growing incidences of antimony resistant parasites and unavailability of true antileishmanial compounds, few drugs like pentamidine (antimicrobial), amphotericin B (antifungal) or miltefosine (antitumor) are currently being used but these are associated with serious side effects. Unfortunately, the emergence of amphotericin B and miltefosine resistant parasites in clinical settings has further questioned their sustained use in leishmanial control. Moreover, the parameters of protective immunity are not well understood in leishmanial pathogenesis therefore, a vaccine candidate, either prophylactic or preventive, is still an unrealized goal. In addition, the emergence of insecticide resistance sand flies in disease endemic regions also stance a big threat for the current elimination strategies. Therefore, in lieu of the limited drug regimen and unavailability of a vaccine, the necessity of a true antileishmanial agent is always there. Although, leishmanial infections have been neglected for many decades but recent studies have identified potential drug targets that could be targeted to control the growth of parasites. In recent past many compounds derived from natural sources have also been shown to possess excellent antiparasitic potential; however, most of these studies are limited to primary evaluation and only a few have reached to clinical levels. In this review, we discuss the limitations of current drug regimen, explore possible drug targets of Leishmania species and summarize wide range of compounds isolated from various natural sources that are worth screening as antileishmanial drug candidates.

1,4-benzothiazine (1,4-B), a pharmacophore of anti-psychotic drug phenothiazines, is a vital class of heterocyclic compounds implicating versatile biological activities. The aim of this review article is to summarize various synthetic strategies, biological activities and structure activity relationship concerning the bioactive heterocycle, 1,4-B. Synthetic chemists have discovered numerous routes for the syntheses of various 1,4-B analogues that show excellent activities through multiple mechanisms. The direct comparison of activities with the parent 1,4-B derivatives enables a systematic analysis of the structure activity relationship (SAR) among the series. This review article is an effort to compile the progress in the chemistry, biological activity and SAR of 1,4-benzothiazine in a systematic way. The previously explored insights included in this article collectively suggests that 1,4-benzothiazines (1,4-Bs), besides offering several interesting biological activities, have a tremendous ability to regulate various types of cancer. The previous work on the present nucleus summarized in this article will help the researchers to design their work based on 1,4-benzothiazine ring.

Tuberculosis (TB) is a primordial infectious disease that mainly affects the lungs. M. tuberculosis (Mycobacterium tuberculosis) is the etiological agent of TB and currently more than one-third of the world population is suffering from TB. For the treatment of TB, administration of multiple antibiotics such as isoniazid, rifampicin, pyrazinamide and ethambutol is required for a long period of time to kill bacteria. However, antibiotic resistance is an emerging problem in multiple drug-resistant tuberculosis (MDR-TB) infections. World Health Organization (WHO) has developed a novel strategy called DOTS (directly observed treatment, short-course), in which specific combination of anti-TB drugs is given to control TB. In this review article we have focused on the comprehensive management of TB and have provided the valuable information about first and second line anti-TB drugs, DOTS and novel drug delivery systems to be used against M. tuberculosis. Important aspects related to new anti-TB drugs and vaccines in various stages of clinical development are also covered in this article.

Drug resistance in Mycobacterium tuberculosis (M. tuberculosis) complicates management of tuberculosis. Efflux pumps contribute to low level resistance and acquisition of additional high level resistance mutations through sub-therapeutic concentrations of intracellular antimycobacterials. Various efflux pump inhibitors (EPIs) have been described for M. tuberculosis but little is known regarding the mechanism of efflux inhibition. As knowledge relating to the mechanism of action and drug target is central to the rational drug design of safe and sufficiently selective EPIs, this review aims to examine recent developments in the study of EPIs in M. tuberculosis from a rational drug development perspective and to provide an overview to facilitate systematic development of therapeutically effective EPIs. Review of literature points to a reduction in cellular energy or direct binding to the efflux pump as likely mechanisms for most EPIs described for M. tuberculosis. This review demonstrates that, where a direct interaction with efflux pumps is expected, both molecular structure and general physicochemical properties should be considered to accurately predict efflux pump substrates and inhibitors. Non-competitive EPIs do not necessarily demonstrate the same requirements as competitive inhibitors and it is therefore essential to differentiate between competitive and non-competitive inhibition to accurately determine structure activity relationships for efflux pump inhibition. It is also evident that there are various similarities between inhibitors of prokaryotic and eukaryotic efflux pumps but, depending on the specific chemical scaffolds under investigation, it may be possible to design EPIs that are less prone to inhibition of human P-glycoprotein, thereby reducing side effects and drug-drug interactions.