Mini Reviews in Medicinal Chemistry - Volume 18, Issue 7, 2018

The serotonin system exerts its effects on the CNS and many peripheral systems. Of the 14 serotonin receptors, the 5-HT7 receptor is the most recently discovered. The 5-HT7 receptor has been shown to be involved in stress reduction, depression, and nociceptive control. Despite the 20 years since the discovery of 5-HT7R, there are still few truly selective ligands. Two of the common scaffolds for 5-HT7R ligands are long chain arylpiperazines (LCAPs) and sulfonamide containing compounds. This review focuses on recently developed (2014-2016) 5-HT7R ligands, their selectivity for the receptor, and suggests the possible new pharmacophore models for these ligands.

Amino acids (AAs) are important nutrients for proliferating tumor cells, and amino acid transport is generally increased in many malignant tumor cells. So far, as a complementary category to 18F-2-fluoro-2-deoxy-D-glucose ([18F]FDG), radiolabeled amino acids that target the upregulated level of amino acid transport have been successfully employed for tumor imaging for decades, thanks to their better differentiation between tumor lesions and inflammation. This review summarizes the development of various radiolabeled amino acid analogues for tumor imaging with single photon emission computed tomography (SPECT) and positron emission tomography (PET) and introduces the basic data related to this area, such as the biological basis, chemical structure, radiolabeling, preclinical evaluation and clinical application. In addition, current status and future prospects of this class of imaging agents are discussed in this review.

Hepatitis C virus (HCV) infection is a major health problem worldwide. Approximately, 170-200 million individuals are chronically infected worldwide and a quarter of these patients are at increased risk of developing liver cirrhosis, hepatocellular carcinoma and even liver failure. A complete eradication of the virus is one of the most important treatment goals for antiviral research. In 2011, the first-generation protease inhibitors boceprevir (BOC) telaprevir (TVR) were approved by FDA as the direct-acting antiviral agents. A number of promising new direct-acting antiviral agents (DAAs) have been developed in the past few years. Due to their increased efficacy, safety, and tolerability, interferon-free oral therapies with DAAs are in use for patients with chronic HCV and cirrhosis patients. In this review, we will discuss the results of clinical trials of several DAAs and the approved combinations, including NS3/4A protease inhibitors, NS5A inhibitors, and NS5B inhibitors. A number of drugs, including Sovaldi®, Harvoni® Viekira Pak®, Epclusa®, Zepatier® have been approved by FDA in the past two-three years. The latest advancement of DAA therapy and related side effects due to the therapy are also discussed.

Chemokines play a significant role in initial and advanced steps of atherogenesis. In early steps, chemokines control the adhesion of leukocytes to endothelial cells (ECs) followed by transmigration of monocytes and their deposition in the intima where they differentiate to proinflammatory macrophages. Except for proinflammatory activity, chemokines are responsible for homeostasis and homing of progenitor cells. Recently, microRNAs (miRs) were found to control expression and activity of chemokines in ECs, vascular smooth muscle cells (VSMCs), and macrophages at different steps of atherogenesis. Expression of the proatherogenic chemokine CXCL1 is suppressed by miR-181 that down-regulates nuclear transcription factor NF-kB stimulation in ECs therefore weakening the adhesiveness of the endothelium for monocytes. MiR-126 activates the endothelial production of a chemokine CXCL12 via self-multiplying feedback loop to promote re-endothelialization and support lesion stability. MiR-155 is proatherogenic by induction of the inflammatory chemokine CCL2 in macrophages. In fact, chemokines, their receptors, and relevant miRs form a complex network that exerts pro- and anti-inflammatory properties in vascular cells during different steps of atherogenic process. Obtaining new information about complicated relations between miRs and chemokines may create prerequisites for the development of novel approaches to treat atherosclerosis.

Aromatase inhibitors are class of drugs that inhibit aromatase, a rate limiting enzyme in the biosynthesis of estrogens from their corresponding androgens. Estrogens play a vital role in the development and growth of breast tumors especially in postmenopausal women apart from their important functions in cell homeostasis. The reduction of estrogen physiological concentration through aromatase inhibition is one of the most important therapeutic strategies against this cancer type. The third-generation aromatase inhibitors are now used as first-line therapy in the treatment of early and metastatic breast cancer in postmenopausal women. However the quest for new class of drugs still stays indispensable to evade the danger of conceivable rising resistances to existing drugs, toxicity and unwanted side effects due to chronic treatment. The current review deals with recent advances in understanding of aromatase, its mechanism and research in the development of various novel chemotypes as aromatase inhibitors. The new challenges and the fast changing trends in bringing rational approach in aromatase inhibitors to a different level like research in dual/multiple target enzyme inhibition strategies, radiolabeling of aromatase inhibitors as theranostic agents; the development of new computational models for complete understanding of aromatase enzyme and its substrate/ligand interactions will bring in holistic approach to comprehensive inhibition of aromatase and other relevant enzymes for effective treatment and monitoring of postmenopausal breast cancer.

Objective: We have synthesized new quinolidinyl-thiazolidinones via Knoevenagel condensation- alkylation reaction, catalyzed by [Et3NH][HSO4]. The present approach offers several advantages such as higher yields, eco-friendly reaction condition and economic availability of the catalyst. Method: The newly synthesized compounds were evaluated for their in vitro antifungal activity against six fungal strains. Some of the synthesized conjugates displayed good to moderate antifungal activity. Conclusion: Again, the molecular docking study performed against the fungal sterol 14α-demethylase (CYP51) showed an excellent binding affinity towards the enzyme which could rationalize the promising antifungal activity portrayed by these derivatives and provides a platform for structure based drug design.

Objective and Background: Hydrazonoyl halides were used as precursors for the synthesis of a new series of bis-spiropyrazoles via reaction with 3,5-diarylidene-piperidone derivatives under ultrasound irradiation. The products were secluded in good yield after short reaction periods. Conclusion: The anticancer activity of bis-spiropyrazoles against HepG2 (hepatic cancer), A549 (lung cancer) and CaCo2 (colon cancer) cell lines was screened. Three tested compounds 4b, 4c and 4f showed promising activity.