Mini Reviews in Medicinal Chemistry - Volume 23, Issue 8, 2023

One of the most fatal infectious diseases, malaria, still poses a threat to about half of the world's population and is the leading cause of death worldwide. The use of artemisinin-based combination therapy has helped to significantly reduce the number of deaths caused by malaria, but the emergence of drug resistance threatens to undo this gain. In a bid to boost adherence, several new combination therapies with effectiveness against drug-resistant parasites are currently being tested in clinical settings. Nevertheless, notwithstanding these gains, malaria must be completely eradicated by a concerted international effort on several fronts. Quinoline-based compounds were the cornerstone of malaria chemotherapy until recently when resistance to these drugs severely hampered efforts to achieve a "Zero Malaria" world. The inappropriate use of available antimalarials is one of the factors responsible for resistance development and treatment failure, warranting the search for new chemical entities and alternative approaches to combat this threat. A vast number of solutions have emerged and one of them, quinoline-hybridization, is an effective method for introducing structural diversity, resulting in molecules with improved biological activities, reduced drug resistance, fewer drug-drug interactions, and improved safety and pharmacokinetic profiles. Choosing the ideal target combination and achieving a balanced activity toward them while preserving drug-like properties are the key challenges in the development of molecular hybrids. This review examines the highlights of quinoline hybridization, with some of the hybrids exhibiting remarkable in vitro and in vivo activities, emphasizing that it is a useful method for developing new anti-malarial lead compounds.

Natural products are an invaluable source for the discovery of drug and pesticide candidates. Piperine, a simple and pungent alkaloid, is isolated from several plants of Piperaceae. Piperine and its derivatives displayed a wide range of biological properties, such as antitumor activity, anti-inflammatory activity, antioxidant activity, neuroprotective activity, insecticidal activity, etc. In recent years, lots of works focused on the biological activities, mechanisms of action, total synthesis, and structural modifications of piperine and its derivatives have been conducted. To the best of our knowledge, however, few review articles related to the biological activities, mechanisms of action, total synthesis, and structural modifications of piperine and its derivatives have been reported to date. Therefore, this review summarizes the research advances (from 2014 to 2020) of piperine and its derivatives regarding bioactivity, mechanisms of action, total synthesis, and structural modifications. Meanwhile, the structure-activity relationships of piperine and its derivatives are also discussed.

Dehydroepiandrosterone (DHEA) is the most abundant steroid hormone in primates, which is predominantly synthesized in the adrenal cortex. A characteristic curve of growth and decline of its synthesis during life was observed, together with the corresponding formation of its sulphate ester (DHEAS). High levels of plasma circulating DHEA are suggested as a marker of human longevity, and various pathophysiological conditions lead to a decreased DHEA level, including adrenal insufficiency, severe systemic diseases, acute stress, and anorexia. More recent studies have established the importance of DHEA in the central nervous system (CNS). A specific intranuclear receptor for DHEA has not yet been identified; however, highly specific membrane receptors have been detected in endothelial cells, the heart, kidney, liver, and the brain. Research shows that DHEA and DHEAS, as well as their metabolites, have a wide range of effects on numerous organs and organ systems, which places them in the group of potential pharmacological agents useful in various clinical entities. Their action as neurosteroids is especially interesting due to potential neuroprotective, pro-cognitive, anxiolytic, and antidepressant effects. Evidence from clinical studies supports the use of DHEA in hypoadrenal individuals and in treating depression and associated cognitive disorders. However, there is also an increasing trend of recreational DHEA misuse in healthy people, as it is classified as a dietary supplement in some countries. This article aims to provide a critical review regarding the biological and pharmacological effects of DHEA, its mechanism of action, and potential therapeutic use, especially in CNS disorders.

Pancreatic ductal adenocarcinoma (PDAC) is one of the highly aggressive malignancies and the leading cause of cancer-related deaths. Despite recent advancements, the overall therapeutic responses in PDAC patients remained relatively low or short-lived. While KRAS is the most frequently mutated proto-oncogene and represents a critical driver, it remains challenging to target all mutant variants. Thus, strategies to target the downstream signaling cascades (RAS-RAF-MEK-ERK) in PDAC were associated with improved response rates. Nevertheless, the activation of other oncogenic cascades, such as PI3K/AKT/mTOR, has also been documented within the same context and implicated in the development of acquired tumor resistance mechanisms and/or reduced efficacy of therapeutic agents. Therefore, an in-depth understanding of overlapping and intersecting pathways is required to overcome the tumor resistance mechanisms to devise novel approaches to enhance the effectiveness of ongoing treatment options. The current review highlights the mechanistic insights from cellular and preclinical studies with particular emphasis on KRAS (i.e., MEK and ERK)-based approaches for PDAC treatment.

Background: Alzheimer’s disease (AD) is an irreversible, progressive and very complex brain disorder. There is still uncertainty about the etiology of AD; however, a few hallmarks like an aggregation of tau proteins, amyloid-β plaques, oxidative stress, low level of choline in the brain etc., play significant roles. Objective: In the present work, we aim to evaluate the recent progress in the development of small organic molecules containing heterocycles like thiazole, pyridines, dihydropyridines, piperidines, pyrrolidines, pyrazoles, quinolines etc. as anti-Alzheimer’s agents. Methods: Several databases, including SciFinder, ScienceDirect, Bentham Science, and PubMed, were searched for relevant articles and reviewed for the present work. Results: Several research groups are actively working on these heterocycle-based compounds as potent single-target inhibitors. Most of the analogues have been evaluated for their cholinesterase (acetylcholinesterase and butyrylcholinesterase) inhibition potential. Several studies have also reported the inhibitory potential of the analogues against MAO-A, MAO-B, and BACE-1 enzymes. However, instead of targeting one enzyme or protein, more than one heterocycle ring is being joined to develop MTDLs (multi-target-directed ligands). Donepezil has become the focal point of anti-AD drug discovery projects. Several research groups have reported various donepezil-based analogues by replacing/ modifying its various ring systems like indanone, piperidine or the methylene linker. Conclusion: Small molecules with nitrogen-containing heterocycles have become the core of drug discovery efforts for AD. With the increasing prominence of the MTDL approach, several new ligands are being discovered as potent anti-AD agents.