Current Topics in Medicinal Chemistry - Volume 16, Issue 11, 2016

The impact of the development of sulfur therapeutics is instrumental to the evolution of the pharmaceutical industry. Sulfur-derived functional groups can be found in a broad range of pharmaceuticals and natural products. For centuries, sulfur continues to maintain its status as the dominating heteroatom integrated into a set of 362 sulfur-containing FDA approved drugs (besides oxygen or nitrogen) through the present. Sulfonamides, thioethers, sulfones and Penicillin are the most common scaffolds in sulfur containing drugs, which are well studied both on synthesis and application during the past decades. In this review, these four moieties in pharmaceuticals and recent advances in the synthesis of the corresponding core scaffolds are presented.

Antimicrobial peptides have recently garnered significant attention as an emerging source of potential antibiotics, due to the swift emergence of multidrug-resistant bacteria and a dwindling antibiotic pipeline. The vast majority of antimicrobial peptides are long, comprised of more than 10 amino acids, resulting in significant production costs for their synthesis while simultaneously displaying metabolic instability and relatively poor pharmacological profiles. To counter these problems, efforts have been shifted to shorter molecules and the development of new peptidomimetic approaches. In this paper, we review promising short, naturally-isolated or synthetic, antimicrobial peptides, along with their mimics, and discuss their merits as potential antibacterial agents.

Nucleoside and nucleobase antimetabolites have substantially impacted treatment of cancer and infections. Their close resemblance to natural analogs gives them the power to interfere with a variety of intracellular targets, which on one hand gives them high potency, but on the other hand incurs severe side effects, especially of the chemotherapeutics used against malignancies. Therefore, the development of novel nucleoside analogs with widened therapeutic windows represents an attractive target to synthetic organic and medicinal chemists. This review discusses the current antimetabolite drugs: 5- fluorouracil, 6-mercaptopurine, 6-thioguanine, Cladribine, Vidaza, Decitabine, Emtricitabine, Abacavir, Sorivudine, Clofarabine, Fludarabine, and Nelarabine; gives insight into the nucleoside drug candidates that are being developed; and outlines the approaches to nucleobase modifications that may help discover novel bioactive nucleoside analogs with the mechanism of action focused on termination of DNA synthesis, which is expected to diminish the off-target toxicity in non-proliferating human cells.

The discovery of nonclassical actions, other than mineral homeostasis, of 1α,25- dihydroxyvitamin D3 (1,25D3) has expanded its applications. Among these, its anti-inflammation activity has drawn more and more attention of researchers to investigate its role in regulating the progression of inflammatory diseases. The expression of many inflammation-related genes is regulated by 1,25D3 through vitamin D receptor (VDR) in a large variety of cells including immune cells such as, but not limited to, macrophages, dendritic cells, T helper cells, and B cells. Studies of 1,25D3 in these immune cells have shown both direct and indirect immunomodulatory activities affecting innate and adaptive immune responses. Moreover, 1,25D3 can also exert its anti-inflammation effects through regulating the biosynthesis of pro-inflammatory molecules in the prostaglandin pathway or through nuclear factor kappa light-chain-enhancer of activated B cells (NFΚB) by affecting cytokine production and inflammatory responses. These actions of 1,25D3 may explain the associations between vitamin D levels and inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, asthma, type 1 diabetes, and systemic lupus erythematosus. Although several analogs of 1,25D3 have shown potent immunomodulatory or anti-inflammatory activity on immune cell cultures or in animal models, no vitamin D analog has been used in clinical research to treat inflammatory diseases. Here, we review the relationship between vitamin D analogs and inflammation based on observations of immune cells, prostaglandin and NFΚB pathways, as well as common inflammatory diseases.

Isatin as an alkaloidal framework have consistently attracted attention of medicinal chemist towards development of wide range of novel therapeutic agents. This review report has discussed significant isatin lead molecules and their derivatives which have shown promising biological potential in recent times. The substituted isatins showing a potent pharmacological activities such as antimicrobial, antitubercular, anticancer, antioxidant, anti-histaminic, anti-HIV, antiviral, anti-inflammatory, anti-Parkinson’s and antidiabetic have been described in this review. The mechanism of action leading to therapeutic activity of the respective isatin derivation has also been recorded. This review reveals that the systematic and rational modifications on isatin motif exhibited significant bio-activities which can be exploited for the development of potent novel therapeutic agents in the future studies. Hence the quest to investigate more structural alterations on isatin scaffold should be continued.

9H-carbazole is an aromatic molecule that is tricyclic in nature, with two benzene rings fused onto a 5-membered pyrrole ring. Obtained from natural sources or by synthetic routes, this scaffold has gained much interest due to its wide range of biological activity upon modifications, including antibacterial, antimalarial, anticancer, and anti-Alzheimer properties. This review reports a survey of the literature on carbazole-containing molecules and their medicinal activities from 2010 through 2015. In particular, we focus on their in vitro and in vivo activities and summarize structure-activity relationships (SAR), mechanisms of action, and/or cytotoxicity/selectivity findings when available to provide future guidance for the development of clinically useful agents from this template.

Thediazabicyclic molecule bispidine named by the chemist Carl Mannich in 1930, is a naturally occurring scaffold with interesting features. Bispidine can form different conformers, has high basicity, can attack dichloromethane, has metal ion coordination properties and interacts with nicotinic acetylcholine receptors. In this review we will discuss important properties, synthetic pathways and biological activities of bispidine and some derivatives. Bispidine can function as a scaffold for compounds with very diverse biological activities, e.g. interacting with ion channels, G-protein coupled receptors, and enzymes, and is even used for the development of new in vivo radiotracers.