Current Medicinal Chemistry - Volume 28, Issue 3, 2021

Background: Monoclonal Antibodies (mAbs) represent one of the most important classes of biotherapeutic agents. They are used to cure many diseases, including cancer, autoimmune diseases, cardiovascular diseases, angiogenesis-related diseases and, more recently also haemophilia. They can be highly varied in terms of format, source, and specificity to improve efficacy and to obtain more targeted applications. This can be achieved by leaving substantially unchanged the basic structural components for paratope clustering. Objectives: The objective was to trace the most relevant findings that have deserved prestigious awards over the years, to report the most important clinical applications and to emphasize their latest emerging therapeutic trends. Results: We report the most relevant milestones and new technologies adopted for antibody development. Recent efforts in generating new engineered antibody-based formats are briefly reviewed. The most important antibody-based molecules that are (or are going to be) used for pharmacological practice have been collected in useful tables. Conclusion: The topics here discussed prove the undisputed role of mAbs as innovative biopharmaceuticals molecules and as vital components of targeted pharmacological therapies.

Background: Neglected Tropical Diseases (NTDs) affect a huge population of the world and the majority of the victims belong to the poor community of the developing countries. Until now, the World Health Organization (WHO) has identified 20 tropical diseases as NTDs that must be addressed with high priority. However, many heterocyclic scaffolds have demonstrated potent therapeutic activity against several NTDs. Objective: There are three major objectives: (1) To discuss the causes, symptoms, and current status of all the 20 NTDs; (2) To explore the available heterocyclic drugs, as well as their mechanisms of action (if known), that are being used to treat NTDs; (3) To develop general awareness on NTDs among the medicinal/health research community and beyond. Methods: The 20 NTDs have been discussed according to their alphabetic orders along with the possible heterocyclic remedies. The current status of treatment with an emphasis on the heterocyclic drugs (commercially available and investigational) has been outlined. In addition, a brief discussion of the impacts of NTDs on socio-economic conditions is included. Results: NTDs are often difficult to diagnose and the problem is worsened by the unhealthy hygiene, improper awareness, and inadequate healthcare in the developing countries where these diseases primarily affect poor people. The statistics include the duration of suffering, the number of individuals affected, and access to healthcare and medication. The mechanisms of action of various heterocyclic drugs, if reported, have been briefly summarized. Conclusion: Scientists and pharmaceutical corporations should allocate more resources to reveal the in-depth mechanism of action of many heterocyclic drugs that are currently being used for the treatment of NTDs. Analysis of current heterocyclic compounds and the development of new medications can help in the fight to reduce/remove the devastating effects of NTDs. An opinion-based concise review has been presented. Based on the available literature, this is the first attempt to present all the 20 NTDs and related heterocyclic compounds under the same umbrella.

Quantum Dots (QDs), whose diameters are often limited to 10 nm, have been of interest to researchers for their unique optical characteristics, which are attributed to quantum confinement. Following their early application in the electrical industry as light-emitting diode materials, semiconductor nanocrystals have continued to show great potential in clinical diagnosis and biomedical applications. The conventional physical and chemical pathways for QD syntheses typically require harsh conditions and hazardous reagents, and these products encounter non-hydrophilic problems due to organic capping ligands when they enter the physiological environment. The natural reducing abilities of living organisms, especially microbes, are then exploited to prepare QDs from available metal precursors. Low-cost and eco-friendly biosynthesis approaches have the potential for further biomedical applications which benefit from the good biocompatibility of protein-coated QDs. The surface biomass offers many binding sites to modify substances or target ligands, therefore achieving multiple functions through simple and efficient operations. Biosynthetic QDs could function as bioimaging and biolabeling agents because of their luminescence properties similar to those of chemical QDs. In addition, extensive research has been carried out on the antibacterial activity, metal ion detection and bioremediation. As a result, this review details the advanced progress of biomedical applications of biosynthesized QDs and illustrates these principles as clearly as possible.

L-type Calcium Channels (LTCCs), also termed as Cav1, belong to voltage-gated calcium channels (VGCCs/Cavs), which play a critical role in a wide spectrum of physiological processes, including neurotransmission, cell cycle, muscular contraction, cardiac action potential and gene expression. Aberrant regulation of calcium channels is involved in neurological, cardiovascular, muscular and psychiatric disorders. Accordingly, LTCCs have been regarded as important drug targets, and a number of LTCC drugs are in clinical use. In this review, the recent development of structures and biological functions of LTCCs are introduced. Moreover, the representative modulators and ligand binding sites of LTCCs are discussed. Finally, molecular modeling and Computer-aided Drug Design (CADD) methods for understanding structure-function relations of LTCCs are summarized.

Ultrasound has been broadly used in biomedicine for both tumor diagnosis as well as therapy. The applications of recent developments in micro/nanotechnology promote the development of ultrasound-based biomedicine, especially in the field of ultrasound-based drug delivery and tumor therapy. Ultrasound can activate nano-sized drug delivery systems by different mechanisms for ultrasound- triggered on-demand drug release targeted only at the tumor sites. Ultrasound Targeted Microbubble Destruction (UTMD) technology can not only increase the permeability of vasculature and cell membrane via sonoporation effect but also achieve in situ conversion of microbubbles into nanoparticles to promote cellular uptake and therapeutic efficacy. Furthermore, High Intensity Focused Ultrasound (HIFU), or Sonodynamic Therapy (SDT), is considered to be one of the most promising and representative non-invasive treatment for cancer. However, their application in the treatment process is still limited due to their critical treatment efficiency issues. Fortunately, recently developed micro/nanotechnology offer an opportunity to solve these problems, thus improving the therapeutic effect of cancer. This review summarizes and discusses the recent developments in the design of micro- and nano- materials for ultrasound-based biomedicine applications.

The prevalence of obesity has tripled in recent decades and is now considered an alarming public health problem. In recent years, a group of endocrine disruptors, known as obesogens, have been directly linked to the obesity epidemic. Its etiology is generally associated with a sedentary lifestyle, a high-fat diet and genetic predisposition, but environmental factors, such as obesogens, have also been reported as contributors for this pathology. In brief, obesogens are exogenous chemical compounds that alter metabolic processes and/or energy balance and appetite, thus predisposing to weight gain. Although this theory is still recent, the number of compounds with suspected obesogenic activity has steadily increased over the years, though many of them remain a matter of debate. Technical-grade chlordane is an organochlorine pesticide widely present in the environment, albeit at low concentrations. Highly lipophilic compounds can be metabolized by humans and animals into more toxic and stable compounds that are stored in fat tissue and consequently pose a danger to the human body, including the physiology of adipose tissue, which plays an important role in weight regulation. In addition, technical-grade chlordane is classified as a persistent organic pollutant, a group of chemicals whose epidemiological studies are associated with metabolic disorders, including obesity. Herein, we discuss the emerging roles of obesogens as threats to public health. We particularly discuss the relevance of chlordane persistence in the environment and how its effects on human and animal health provide evidence for its role as an endocrine disruptor with possible obesogenic activity.

Background: Inflammation is the body’s immune system’s fast coordinating response to irritants caused by pathogens, external injuries, and chemical or radiation effects. The nucleotidebinding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a critical component of the innate immune system. The dysfunction of NLRP3 inflammasome contributes to various pathogeneses of complex diseases, such as uncontrolled infection, autoimmune diseases, neurodegenerative diseases, and metabolic disorders. This review describes recent progress on the discovery of NLRP3 inflammasome inhibitors and their therapeutic potential. Methods: Based on the mechanism of NLRP3 activation, several types of NLRP3 inhibitors are described and summarized according to their origins, structures, bioactivity, and mechanism of action. Structure-Activity Relationship (SAR) is also listed for different scaffolds, as well as effective pharmacophore. Results: Over one-hundred papers were included in the review. The development of NLRP3 inhibitors has been described from the earliest glyburide in 2001 to the latest progress in 2019. Several series of inhibitors have been categorized, such as JC-series based on glyburide and BC-series based on 2APB. Many other small molecules such as NLRP3 inhibitors are also listed. SAR, application in related therapeutic models, and five different action mechanisms are described. Conclusion: The findings of this review confirmed the importance of developing NLRP3 inflammasome inhibitors. Various NLRP3 inhibitors have been discovered as effective therapeutic treatments for multiple diseases, such as type II diabetes, experimental autoimmune encephalomyelitis, stressrelated mood disorders, etc. The development of a full range of NLRP3 inflammasome inhibitors is still at its foundational phase. We are looking forward to the identification of inhibitory agents that provide the most potent therapeutic strategies and efficiently treat NLRP3 inflammasome-related inflammatory diseases.

Infections caused by Trypanosoma brucei, Trypanosoma cruzi, Leishmania spp., Entamoeba histolytica, Giardia lamblia, Plasmodium spp., and Trichomonas vaginalis, are part of a large list of human parasitic diseases. Together, they cause more than 500 million infections per year. These protozoa parasites affect both low- and high-income countries and their pharmacological treatments are limited. Therefore, new and more effective drugs in preclinical development could improve overall therapy for parasitic infections even when their mechanisms of action are unknown. In this review, a number of heterocyclic compounds (diamidine, guanidine, quinoline, benzimidazole, thiazole, diazanaphthalene, and their derivatives) reported as antiprotozoal agents are discussed as options for developing new pharmacological treatments for parasitic diseases.

c-Jun N-Terminal Kinases (JNKs), members of the Mitogen-Activated Protein Kinase (MAPK) signaling pathway, play a key role in the pathogenesis of many diseases including cancer, inflammation, Parkinson’s disease, Alzheimer’s disease, cardiovascular disease, obesity, and diabetes. Therefore, JNKs represent new and excellent target by therapeutic agents. Many JNK inhibitors based on different molecular scaffolds have been discovered in the past decade. However, only a few of them have advanced to clinical trials. The major obstacle for the development of JNK inhibitors as therapeutic agents is the JNKisoform selectivity. In this review, we describe the recent development of JNK inhibitors, including ATP competitive and ATP non-competitive (allosteric) inhibitors, bidentatebinding inhibitors and dual inhibitors, the challenges, and the future direction of JNK inhibitors as potential therapeutic agents.

1-Deoxynojirimycin (1-DNJ) is a naturally occurring sugar analogue with unique bioactivities. It is found in mulberry leaves and silkworms, as well as in the metabolites of certain microorganisms, including Streptomyces and Bacillus. 1-DNJ is a potent α-glucosidase inhibitor and it possesses anti-hyperglycemic, anti-obese, anti-viral and anti-tumor properties. Some derivatives of 1-DNJ, like miglitol, miglustat and migalastat, were applied clinically to treat diseases such as diabetes and lysosomal storage disorders. The present review focused on the extraction, determination, pharmacokinetics and bioactivity of 1-DNJ, as well as the clinical application of 1-DNJ derivatives.