Mini Reviews in Medicinal Chemistry - Volume 13, Issue 11, 2013

Chelation therapy plays a prominent role in the clinical treatment of metal intoxication. In this paper the principal causes of metal toxicity are exposed, and the chemical and biomedical requisites of a chelating agent are sketched. The chelating agents currently in use for scavenging toxic metal ions from humans belong to few categories: those characterized by coordinating mercapto groups, by oxygen groups, poliaminocarboxylic acids, and dithiocarbamates. Considering that the complex formation equilibria have been studied for less than 50% of chelators in use, some reflections on the utility of stability constants are presented, together with an evaluation of ligands under the stability profile. The competition between endogenous and toxic target metal ions for the same chelating agent is furthermore examined. A thorough examination of stability constant databases has allowed to select, for each toxic metal, the ligands distinguished by the best pMe values. Even though this selection does not consider the biomedical requisites of a chelating agent, it gives a clear picture both of the pMe values that can be attained, and of the most appropriate chelators for each metal ion.

Authorities of Drug Administration in the United States of America approved about 5000 drugs for use in the therapy or management of several diseases. About two hundred of these drugs have active metabolites and the knowledge of their medicinal chemistry is important both in medical practice and pharmaceutical research. This review gives a detailed description of the medicinal chemistry of drugs with active metabolites generated after conjugation. This review focused on glucuronide-, acetyl-, sulphate- and phosphate-conjugation of drugs, converting the drug into an active metabolite. This conversion essentially changed the lipophilicity of the drug.

Tubulysins are a family of natural tetrapeptides in clinical development as a consequence of their potent anticancer activity, even for multi-drug resistant carcinoma. Tubulysins inhibit tubulin polymerization by binding to the peptide binding site located near the vinca alkaloid binding site of tubulin. The limited availability and pharmacological profile of the tubulysins attracted synthetic and medicinal chemists to initiate programs towards their total synthesis. This paper reviews efforts toward the total synthesis of tubulysins and selected structure-activity relationship studies of tubulysin analogs.

Even though protein tyrosine phosphatase has been identified as a validated therapeutic target over a decade for type II diabetes and obesity, developing a selective inhibitor to protein tyrosine phosphatase 1B (PTP1B) over other cellular PTPases has been a complicated task owing to the highly conserved and polar nature of the PTP1B catalytic site. Virtual screening study of in-house chemical depository resulted in the prioritization of few low molecular weight compounds as PTP1B inhibitors. The in-vitro pNPP assays were carried out on prioritized compounds in both PTP1B and T-cell protein tyrosine phosphatase (TCPTP). From this we identified four low molecular weight compounds as PTP1B inhibitors, of which the compound AU-2439 has shown 5 fold selectivity towards PTP1B over highly homologous TCPTP. In this short communication selectivity of AU-2439 is explained based on interaction with critical active site residues in both proteins using docking models.

Pyrazine is one of the important class of heterocyclic compounds that can be obtained naturally or synthesized chemically. Pyrazine ring has got importance in exhibiting various biological activities in association with other scaffolds like pyrrole, pyrazole, imidazole, triazole, tetrazole, thiophene, oxazole, pyridine, piperidine and piperazine. Presence of pyrazine ring as a basic scaffold in various clinically used drugs exhibits its importance in drug design. In this review, attempt has been made to disclose various therapeutic applications of pyrazine derivatives reported during the last decade.

Imidazoles are one of the most promising and vigorously pursued areas of contemporary antifungal chemotherapy depicting broad spectrum and potent activity. They have relatively simple molecular nucleus, which is amenable to many structural modifications. These agents have several favorable properties such as excellent bioavailability, good tissue penetrability and permeability and a relatively low incidence of adverse and toxic effects. They have been found effective in the treatment of various infectious diseases. This paper is an attempt to review the therapeutic potential of imidazoles as antifungal with an updated account on their development.

Recent developments and novel research strategies are adopted widely to discover and develop the new drugs to treat tuberculosis. New antitubercular drugs are urgently needed because tuberculosis remains a global health problem as around nine million new cases are estimated each year with almost two million fatalities. It states the impact and outcomes that have made a significant effect in antitubercular drug development. We are presenting current status of tuberculosis, antitubercular drug development, novel molecular targets, novel agents in clinical and pre-clinical development and some efforts that are being made in the development of novel molecules based on different pharmacophores as lead compounds and recent strategies.

Irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) are highly prevalent gastrointestinal disorders. Traditional symptoms based therapies had somewhat limited success and efficacy in addressing the disorders. Recently,linaclotide emerged as novel peptide capable of improving abdominal symptoms in patients suffering from IBS-C and CIC. Guanylate cyclase C (GC-C) receptor a multi domain protein, found to be molecular target for linaclotide which acts by activating GC-C receptor on the apical surface of intestinal epithelial cells. Binding of linaclotide to GC-C receptor triggers the elevation of second messenger cGMP that elicits fluid secretion into intestinal cells which play a critical role in maintaining homeostasis through cystic fibrosis transmembrane conductance regulator (CFTR). Data from Phase and clinical trials demonstrated that linaclotide seems to produce a statisticall significant increase in stool frequency, improved straining, decreased abdominal pain and discomfort.