Mini Reviews in Medicinal Chemistry - Online First

The global escalation of Multidrug-Resistant (MDR) bacterial infections poses a serious and growing threat to public health, contributing to increased morbidity, mortality, and substantial economic burden worldwide. The widespread and often indiscriminate use of antibiotics in clinical and agricultural settings has accelerated the emergence of resistance, significantly diminishing the efficacy of conventional antimicrobial therapies. This pressing challenge necessitates the exploration of alternative sources for novel antibiotics. Marine ecosystems-renowned for their immense biodiversity and ecological complexity-have gained attention as a rich and largely untapped reservoir of bioactive natural products with potent antimicrobial activity. Marine organisms, such as sponges, tunicates, algae, and bacteria and fungi derived from marine sources, produce structurally diverse and pharmacologically active metabolites, including peptides, polyketides, alkaloids, terpenoids, sterols, lactones, and halogenated compounds. Many of these marine-derived molecules possess unique chemical scaffolds and novel mechanisms of action, offering the potential to circumvent existing resistance pathways. Some compounds have shown promising activity against MDR pathogens, including Staphylococcus aureus, Pseudomonas aeruginosa, and Acinetobacter baumannii. However, challenges such as low natural abundance, difficulty in cultivation, and structural complexity have limited their clinical translation. Recent advancements in marine biotechnology, genomics, metagenomics, and synthetic biology have opened new avenues for the discovery, biosynthesis, and structural optimization of these compounds. These innovative approaches not only facilitate sustainable production but also enhance the pharmacological properties.

Prolactinomas are the most common neuroendocrine tumors of the pituitary and the leading cause of hyperprolactinemia. Dopamine Receptor Agonists (DAs), particularly cabergoline (CAB), effectively reduce prolactin levels and tumor volume, and are therefore the first-line therapy for prolactinomas. With long-term cabergoline use, adverse effects may become more consequential for some patients. Cabergoline-Associated Valvulopathy (CAV) primarily affects the mitral, tricuspid, and aortic valves, although its underlying mechanisms remain unclear. The potential link between CAB use and Valvular Heart Disease (VHD) in patients with prolactinomas remains controversial. This review summarizes current understanding of CAV and explores potential molecular mechanisms, including CAB’s modulation of catecholaminergic, serotonergic, and Transforming Growth Factor-beta(TGF-β) related signaling pathways, along with inflammatory pathways. By integrating clinical patterns with mechanistic plausibility, we aim to support practical surveillance decisions and improve the long-term safety of CAB therapy in patients with prolactinomas.

In most industrialized and developing nations, breast cancer is the second most prevalent and prominently occurring cancer among females, as well as the primary cause of mortality in women (affecting about 30% of newly diagnosed patients annually). Currently, there are several highly advanced and specialized treatment options for breast cancer, including immunotherapy, hormone therapy, surgery, radiotherapy, and chemotherapy, posing subsequent additional challenges, like toxicity, non-specific drug distribution, multidrug resistance, and high cost of treatment. To counter these Side effects, several natural products are used as replacements and adjuvant medicines, and have also gained attention for their safety, efficacy, and cost-effectiveness. A number of clinical and preclinical studies have shown that a combination of natural dietary components and chemotherapeutics has progressively promoted apoptosis, inhibited cellular proliferation, and mobilized the immune system via modulating different signaling pathways. Phytochemicals like curcumin, Berberine, resveratrol, Evodiamine, and plumbagin act synergistically along with chemotherapeutics, resulting in inhibition of cell proliferation, induction of apoptosis, and cell cycle arrest of cancer cells. This thorough analysis focuses on the most recent cancer treatments for breast cancer, which include the use of synthetic and phytochemical medications in combination with synthetic chemotherapeutic drugs to provide concomitant treatment of breast carcinomas.

Schiff bases are organic compounds that were first discovered in 1864 by German chemist Hugo Schiff. These bases result from a condensation reaction between a primary amine and a carbonyl compound, usually an aldehyde or a ketone. This reaction eliminates a water molecule and forms an imine group (-C=N-), the characteristic feature of Schiff bases. These bases are widely studied for their simple synthesis, structural diversity, and numerous applications in pharmacology. This review discusses their general structures and methods of synthesis. Schiff bases can be classified according to their structure (aliphatic or aromatic), denticity, and symmetry. Schiff bases have the ability to coordinate with metal ions such as copper (Cu²⁺), zinc (Zn²⁺), cobalt (Co²⁺), or nickel (Ni²⁺), allowing the formation of stable metal complexes, which enhances their biological properties. At the biological level, Schiff bases exhibit a wide range of activities due to their imine group. These include antibacterial, antifungal, antiviral, antitubercular, anti-inflammatory, antioxidant, anticancer, and other activities. This biological activity can be enhanced when Schiff bases complex with transition metals. In silico approaches play a crucial role in evaluating the therapeutic potential of Schiff bases and their complexes. These methods help predict their pharmacokinetic properties and binding affinity, thereby facilitating the rational design of more potent and selective therapeutic agents.

Psilocybin, chemically known as (4-phosphoryloxy-N, N-dimethyltryptamine, 4-PO-DMT), is derived from the psychoactive mushroom genus, Psilocybe. Of the four active metabolites, psilocin readily enters systemic circulation. The psychoactive effects of psilocin are thought to arise through partial agonist effects at the 5-HT2A receptor. Psychedelic drugs, including psilocybin, are having a renaissance, especially in mental health disorders, addiction, and cancer-related depression. The beneficial effects of psilocybin are expanding into brain injury and lifespan due to its ability to enhance neuroplasticity. However, the large-scale synthesis of psilocybin was the main challenge for the scientific community after the FDA’s breakthrough therapy designation in 2018 for Treatment-Resistant Depression (TRD) and for Major Depressive Disorder (MDD) in 2019. Synthesizing psilocybin is challenging due to the complex reactions, a multi-step process that requires strict temperature control, hazardous reagents, and purification difficulties. The very first Hoffman’s synthetic method was successfully modified by several medicinal chemistry research groups to obtain it on a kilogram scale to conduct important clinical trials. This mini review comprises a brief history, chemistry, and pharmacology, along with the therapeutic use in depression of this naturally occurring psychedelic.

Quinone derivatives are redox-modulating scaffolds with notable antioxidant properties. Quinones are naturally occurring and synthetic conjugated cyclic diketones. Owing to their structural and chemical diversity, quinones possess diverse biological and pharmacological properties, including redox signaling, oxidative stress reduction, and modulation of redox cycling. They activate the nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway, a transcription factor responsible for cellular antioxidant defenses via their electrophilic interactions with cysteine residues in Kelch-like ECH-associated protein 1 (KEAP1) and consequent nuclear translocation of NRF2. They also scavenge free radicals. The ability to scavenge free radicals and modulate the NRF2 signaling pathway makes quinone derivatives therapeutic molecules in oxidative stress-mediated diseases. However, excessive exposure to quinones has been linked to toxicity and pro-oxidant consequences. Therefore, regulating quinone concentration is required to address toxicological issues. Despite their structural and functional diversity, structural adjustments for some quinones based on structure-activity relationship (SAR) analysis will be necessary to enhance their toxicological profile and therapeutic effects. Additionally, strategies such as controlled dosing and targeted delivery systems can be employed to address toxicological concerns and enhance the therapeutic potential of quinone derivatives. The current review provides comprehensive information on the NRF2-inducing activity, radical scavenging activity, therapeutic potential, and toxicological profile of quinone derivatives as redox-modulating agents.

Alzheimer’s disease (AD) is the predominant type of dementia, emerging as a major health issue globally due to its increasing incidence and the limited approved therapies that provide only symptomatic relief. Adamantane, a diamondoid hydrocarbon with a distinctive cage-like structure, has emerged as a promising scaffold in medicinal chemistry due to its high lipophilicity, leading to good central nervous system bioavailability. Notably, memantine, an NMDA (N-methyl-d-aspartate) receptor antagonist, is an adamantane derivative that is approved by the U.S. Food and Drug Administration (US FDA) to manage moderate-to-severe AD symptoms. This review analyses the structure-activity relationship (SAR) of several adamantane derivatives and their relevance to AD. Amino-substituted adamantanes, such as amantadine and memantine, display anti-Alzheimer potential due to improved NMDA receptor affinity and CNS permeability. Additional targets, such as voltage-gated sodium channels and retinoid receptors, are proposed as potential targets for adamantane derivatives developed to act against AD. While various adamantane compounds have been patented and studied, few have become clinically approved drugs. Structural changes, particularly at bridgehead carbon atoms, greatly influence pharmaceutical results. Adamantane's physicochemical features make it a preferred framework for future CNS-targeted therapies. Given the increasing need for more effective AD treatments, adamantane-based compounds present a viable option for new drug development.

Argemone mexicana (Linn.), commonly known as prickly poppy, is a well-documented medicinal plant in Indian Ayurvedic literature, recognized for its diverse pharmacological properties. It has been investigated for its potential applications in the treatment of cancer, inflammation, and wound healing, thereby highlighting its pharmacological significance. Traditionally, it has been used successfully to treat skin diseases, ulcers, tumors, boils, and snake venom poisoning. The therapeutic potential of this plant has been further validated by recent studies, which also demonstrated its safety in clinical trials for antimalarial activity.

Berberine, argemonine, argenaxine, and chelerythrine are among the bioactive alkaloids abundant in Argemone mexicana, shown to possess significant anticancer, antibacterial, anti-inflammatory, and antimalarial properties. These compounds exert cytotoxic effects against various cancer cell lines by modulating key oncogenic pathways and preventing the acquisition of cancer hallmark characteristics, such as uncontrolled proliferation, apoptosis evasion, inflammation, invasion, angiogenesis, and drug resistance.

Preclinical studies have further explored the role of Argemone mexicana in cancer treatment and wound healing, expanding its pharmacological relevance. This review systematically compiles evidence from in vitro and in vivo studies, elucidating the mechanisms through which Argemone mexicana and its derived compounds exhibit anticancer activity. By highlighting its potential as a natural source of anticancer agents, this review aims to provide a foundation for future research and the development of novel plant-based cancer therapeutics.

Metabolic syndrome is characterized by a combination of conditions, including abdominal obesity, elevated blood pressure, increased blood sugar levels, and high triglycerides. The incidence of metabolic syndrome is concerningly increasing worldwide. Metabolic syndrome increases the risk of cardiovascular diseases, type 2 diabetes mellitus, non-alcoholic fatty liver disease, chronic kidney disease, and even cancer. Cholelithiasis refers to the formation of gallstones. Metabolic associations, including dyslipidemia, obesity, diabetes, and insulin resistance, are all risk factors for cholelithiasis. Modifiable factors include changes in lifestyle and metabolic conditions. In this narrative review, we searched the PubMed, Scopus, and Google Scholar databases to identify evidence-based literature on the association between metabolic syndrome and cholelithiasis. We discuss the biochemical reaction underlying cholelithiasis, the receptors and signaling pathways involved, and therapeutic options targeting hepatic cholesterol synthesis and secretion. We discuss the molecular mechanisms underlying the association between metabolic syndrome and cholelithiasis, including insulin resistance, genetic factors, and gallbladder functions relevant to cholelithiasis. The clinical implications, along with surgical interventions and treatment, are also discussed in detail. The review may benefit physicians involved in the treatment of cholelithiasis and metabolic syndrome, and help researchers develop appropriate drugs in the future.