Pyridine-based ring systems are one of the most extensively used heterocycles in the field of drug design, primarily due to their profound effect on pharmacological activity, which has led to the discovery of numerous broad-spectrum therapeutic agents. In the US FDA database, there are 95 approved pharmaceuticals that stem from pyridine or dihydropyridine, including isoniazid and ethionamide (tuberculosis), delavirdine (HIV/AIDS), abiraterone acetate (prostate cancer), tacrine (Alzheimer’s), ciclopirox (ringworm and athlete’s foot), crizotinib (cancer), nifedipine (Raynaud’s syndrome and premature birth), piroxicam (NSAID for arthritis), nilvadipine (hypertension), roflumilast (COPD), pyridostigmine (myasthenia gravis), and many more. Their remarkable therapeutic applications have encouraged researchers to prepare a larger number of biologically active compounds decorated with pyridine or dihydropyridine, expandeing the scope of finding a cure for other ailments. It is thus anticipated that myriad new pharmaceuticals containing the two heterocycles will be available in the forthcoming decade. This review examines the prospects of highly potent bioactive molecules to emphasize the advantages of using pyridine and dihydropyridine in drug design. We cover the most recent developments from 2010 to date, highlighting the ever-expanding role of both scaffolds in the field of medicinal chemistry and drug development.

Genistein (GE) was reported to exert a wide spectrum of biological activities, including antioxidant, anti-inflammatory, anti-mutagenic, anticancer, and cardio-protective effects. In addition, both clinical and preclinical studies have recently suggested GE a potential neuroprotective and memory-enhancing drug against neurodegenerative diseases. The animal model of scopolamine (Scop)-induced amnesia is widely used to study underlying mechanisms and treatment of cognitive impairment in neurodegenerative diseases. However, there is no report about the effects of GE on Scop-induced amnesia in mice. Therefore, the present study was carried out to investigate the beneficial effects and potential mechanism of GE against Scop-induced deficits in mice. The mice were orally pretreated with either GE (10, 20, and 40 mg/kg) or donepezil (1.60 mg/kg) for 14 days. After the pretreatment, the open field test was conducted to assess the effect of GE on the locomotor activity of mice. Thereafter, mice were daily injected with Scop (0.75 mg/kg) intraperitoneally to induce memory deficits and subjected to the cognitive behavioral tests including the Object Location Recognition (OLR) experiment and Morris Water Maze (MWM) task. After the behavioral tests, biochemical parameter assay and western blot analysis were used to examine the underlying mechanisms of its action. The results showed that GE administration significantly improved the cognitive performance of Scop-treated mice in OLR and Morris water maze tests, exerting the memory-enhancing effects. Additionally, GE remarkably promoted the cholinergic neurotransmission and protected against the oxidative stress damage in the hippocampus of Scop-treated mice, as indicated by decreasing AChE activity, elevating ChAT activity and Ach level, increasing SOD activity, lowering the level of MDA and increasing GSH content. Furthermore, GE was found to significantly upregulate the expression levels of p-ERK, p-CREB and BDNF proteins in the hippocampus of Scop-treated mice. Taken together, these results for the first time found that GE exerts cognitive-improving effects in Scop-induced amnesia and suggested it may be a potential candidate compound for the treatment of some neurodegenerative diseases such as Alzheimer’s Disease (AD).

In the recent years, interest in soybean as a neuroprotective nutrient in the management of Alzheimer’s disease (AD) has increased and soy isoflavones (SI), as kinds of soybean phytochemicals, are thought to be biologically active components that confer this beneficial effect against neurodegenerative diseases. However, the neuroprotective effect of SI is not well understood. Therefore, the present study (30 days) was conducted to investigate the neuroprotective effects of soy isoflavones (SI) on scopolamine (SCOP)-induced memory impairments in Institute of Cancer Research (ICR) mice (aged 4 weeks) and to elucidate its underlying mechanisms of action. SI (40 mg/kg) administration improved the cognitive performance of SCOP-treated mice in an object location recognition task and the Morris water maze test. SI (40 mg/kg) administration significantly enhanced cholinergic system function and suppressed oxidative stress levels in the hippocampus of SCOP-treated mice. Furthermore, SI (40 mg/kg) treatment markedly upregulated the phosphorylation levels of extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) expression levels in the hippocampus. Taken together, these results demonstrated that soy isoflavones exerted a significant neuroprotective effect on cognitive dysfunctions induced by scopolamine, suggesting that soy isoflavones could be a good candidate for possible treatment of neurodegenerative diseases, such as Alzheimer’s disease (AD).

Ochratoxin A (OTA) is a potent nephrotoxic, hepatotoxic, and teratogenic compound which is a significant mycotoxin contaminates cereals during storage. Aspergillus ochraceus is the most common producer of OTA in cereals and cereal-derived products. Cinnamaldehyde is a natural substance derived from plant cinnamon playing an important role in the reduction of OTA contamination. In this study, the antifungal and antitoxigenic effect of cinnamaldehyde was investigated with its mechanisms of inhibition of fungal growth at the morphological and ultrastructural levels, and inhibition of OTA biosynthesis at the transcriptional level. Significant A. ochraceus growth was inhibited at 0.4–1.6 mmol/L with fumigation. A. ochraceus exposed to 0.4 mmol/L of cinnamaldehyde indicated irreversible harmful morphological and ultrastructural modifications such as the folding of the cell, the loss of integrity of the cell wall, the disruption of plasma membrane, the destruction of the mitochondria, and the absence of intracellular organelles. These alterations may be attributed to its inhibition of enzymatic reactions that regulate cell wall synthesis, thus disturbing the morphogenesis and growth of A. ochraceus. In the presence of cinnamaldehyde, the tested biosynthetic and regulatory genes like pks, nrps, veA, laeA and velB were highly downregulated. Moreover, the downregulation effect of cinnamaldehyde increased proportionally with the concentrations. These results suggest that the decrease of OTA production by cinnamaldehyde is attributed to the downregulation of the transcriptional levels of OTA biosynthetic and regulatory genes besides the inhibition of fungal growth. The study reveals the mechanisms of the antifungal and antitoxigenic activities of cinnamaldehyde against A. ochraceus, and further emphasizes that cinnamaldehyde could be a safe and effective natural agents against OTA contamination during cereals storage.