Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents) - Volume 21, Issue 2, 2023

Obstructive hypertrophic cardiomyopathy results from asymmetric septal hypertrophy, which eventually obstructs the outflow of the left ventricle. Obstructive hypertrophic cardiomyopathy is linked to mutations in genes that encode for sarcomere proteins, including actin, β-myosin heavy chain, titin, and troponin. The mutations lead to structural abnormalities in myocytes and myofibrils, causing conduction irregularities and abnormal force generation. Obstructive hypertrophic cardiomyopathy is a chronic disease that worsens over time, and patients become at higher risk of developing atrial fibrillation, heart failure, and stroke. Up until recently, there were no disease- specific medications for obstructive hypertrophic cardiomyopathy. Nevertheless, the US Food and Drug Administration approved mavacamten on April 28, 2022, for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (New York Heart Association class II to III) in adults to improve functional capacity and symptoms. Its approval was based on data from EXPLORER- HCM and EXPLORER-LTE (NCT03723655). Mavacamten is a novel, first-in-class, orally active, allosteric inhibitor of cardiac myosin ATPase, which decreases the formation of actin- myosin cross-bridges, and thus, it reduces myocardial contractility, and it improves myocardial energetics. It represents a paradigm-shifting pharmacological treatment of obstructive hypertrophic cardiomyopathy. In this review, we describe its chemical and mechanistic aspects as well as its pharmacokinetics, adverse effects and warnings, potential drug-drug interactions, and contraindications.

Aged garlic extract (AGE) is an odorless derivative of garlic prepared by extracting garlic cloves in an aqueous solution for twenty months. During the process of aging, reactive organosulfur compounds such as allicin present in garlic are converted to their stable isoforms such as S- Allyl cysteine. The unstable organo sulfurs in garlic (Allium sativum L.) have been reported to cause problems in the gastrointestinal (GI) tract with an extremely pungent odor to attain its therapeutic potential. But these pharmacologically safer sulfur compounds of AGE have been studied and reported to have exceptional therapeutic potential in human health and various diseases. SAllyl cysteine (SAC), Diallyl disulfide (DADS), Diallyl trisulfide (DATS), S-allyl-mercaptocysteine (SAMC), are the most studied organosulfur compounds in in-vitro as well as in-vivo research. Biomedical research suggests that these phytoconstituents exhibit antioxidant, cardioprotective, cancer preventive, neuroprotective, immunomodulatory, antilipidemic, antidiabetic, hepatoprotective, and antiobesity effects. The therapeutic potential of aged garlic extract has been found to be extensively beneficial in these conditions, and provide a vast future in biomedical chemistry, herbdrug synergy and drug designing. The purpose of this review is to provide a mechanistic understanding of various organosulfur compounds of AGE in human health and disease based on data provided in the literature.

Surgery, radiation, chemotherapy, and targeted therapy were the four basic kinds of cancer treatment until recently. Immuno-oncology (IO), or the concept that cancer cells were damaged by activating the body's immune system, has emerged and is explained as a unique and crucial method for treating different cancers over the last decade. The US Food and Drug Administration and the European Medicines Agency both approved this newly recognized way of treating cancer in 2020. Within IO, different therapeutic classes have arisen, which are the subject of this article. Immune checkpoint inhibitors are currently the most well-known therapeutic class of immuno-oncology medications due to their amazing ability to show efficacy in a variety of tumor types. Biomarkers were tested for different tumors like gastrointestinal cancer, whole Head, lower and upper part Neck cancer, and also cervical cancer by programmed death-ligand 1 (PD-L1) check point and their targets and are currently being utilized prior to treatment by using Pembrolizumab. However, the significance of PD-L1 expression for immune check point reticence therapy in other/different onco-cancer types remains unclear. Homogenized immuneoncology drugs with regular therapy have been recently studied and clinical efficacy outcomes have shown to be significantly improved. While IO agents are fast transforming the marketed treatment for cancer patients, there are still a number of obstacles to overcome in terms of associating their adverse effects and confirming those different healthcare systems, such as financing these expensive therapies. In addition to cancer vaccines and chimeric antigen receptor T-cell treatments, other IO drugs are in pipeline containing chimeric antigen receptor T-cell therapies; earlier ones have their own set of toxicities and high cost related challenges.

Background: Human factor XIIa (FXIIa) is a plasma serine protease that plays a significant role in several physiological and pathological processes. Animal models have revealed an important contribution of FXIIa to thromboembolic diseases. Remarkably, animals and patients with FXII deficiency appear to have normal hemostasis. Thus, FXIIa inhibition may serve as a promising therapeutic strategy to attain safer and more effective anticoagulation. Very few small molecule inhibitors of FXIIa have been reported. We synthesized and investigated a focused library of triazol-1-yl benzamide derivatives for FXIIa inhibition. Methods: We chemically synthesized, characterized, and investigated a focused library of triazol- 1-yl benzamide derivatives for FXIIa inhibition. Using a standardized chromogenic substrate hydrolysis assay, the derivatives were evaluated for inhibiting human FXIIa. Their selectivity over other clotting factors was also evaluated using the corresponding substrate hydrolysis assays. The best inhibitor affinity to FXIIa was also determined using fluorescence spectroscopy. Effects on the clotting times (prothrombin time (PT) and activated partial thromboplastin time (APTT)) of human plasma were also studied. Results: We identified a specific derivative (1) as the most potent inhibitor in this series. The inhibitor exhibited nanomolar binding affinity to FXIIa. It also exhibited significant selectivity against several serine proteases. It also selectively doubled the activated partial thromboplastin time of human plasma. Conclusion: Overall, this work puts forward inhibitor 1 as a potent and selective inhibitor of FXIIa for further development as an anticoagulant.

Aims: This study aimed to investigate the antidiabetic activity of Artemisia arborescens. Background: Artemisia arborescens is an aromatic, medicinal, and endemic plant mostly found in the Mediterranean region. This plant is widely used as alternative medicine. Objective: The study was designed to examine the antihyperglycemic and antihyperlipidemic activities of Artemisia arborescens aqueous extract (AEAA) in normal and streptozotocin (STZ)- induced diabetic rats. Methods: The effect of AEAA (40 mg/kg and 80 mg/kg) on plasma glucose levels and plasma lipid profile was investigated in normal and STZ-induced diabetic rats. The plasma glucose levels were determined after a single (6 hours) and subchronic oral administration (7 days), and plasma lipid profiles were evaluated after both acute and subchronic oral administration. Additionally, the glycogen content in the liver, extensor digitorum longus (EDL), and soleus muscles was measured using a standard method. Moreover, the aqueous extract was tested for its 1.1-diphenyl-2- picrylhydrazyl (DPPH) radical-scavenging activity. Results: In diabetic rats, AEAA oral administration (40 mg/kg and 80 mg/kg) produced a significant decrease in blood glucose levels after 7 days of oral administration (P<0.0001). Moreover, a significant decrease in plasma triglyceride levels was reported on the last day of treatment by AEAA (80 mg/kg) (P<0.05). Furthermore, a significant decrease in total cholesterol levels was observed after 7 days of AEAA oral administration in diabetic rats (P<0.01). Moreover, a significant increase in HDL-c concentration was noted after one week of AEAA (80 mg/kg) oral administration (P<0.001). In addition, AEAA oral administration (80 mg/kg) significantly increased the glycogen content in the liver and extensor digitorum longus (P<0.05). On the other hand, qualitative and quantitative phytochemical screenings revealed the presence of various compounds, such as polyphenols, flavonoids, and tannins. Conclusion: In summary, the study demonstrates that Artemisia arborescens oral administration exhibited a significant antihyperglycemic effect on diabetic rats and revealed a significant amelioration in lipid profile and glycogen content.

Aims: The work aimed to study the antihypertensive ability of Haloxylon scoparium. Background: Haloxylon scoparium Pomel is used to treat various diseases, including hypertension. Objective: This study aimed to evaluate the antihypertensive effect of Haloxylon scoparium (H. scoparium) in hypertensive rats, and to evaluate its probable vasorelaxant activity. Materials and Methods: The aqueous extract of Haloxylon scoparium (AEHS) was prepared and used to investigate its antihypertensive ability in L-NAME(Nω-L-arginine methyl ester)-induced hypertensive rats, and its vasorelaxant activity was studied on the isolated thoracic aorta of rats. The acute and subchronic effects of (AEHS) on blood pressure parameters were evaluated after oral administration of AEHS (60 and 100 mg/kg body weight) for 6 h for the acute experiment and for 7 days for the subchronic test. Results: The results indicated that AEHS decreased blood pressure parameters (systolic, mean, and diastolic blood pressure) after repeated oral administration in hypertensive rats without affecting normal rats. In addition, AEHS (375-1250 μg/mL) revealed a vasorelaxant effect in thoracic aortic rings precontracted with norepinephrine (NE) (10 μM) or KCl (80 mM). This effect was partially decreased in the presence of nifedipine by inhibition of the vascular calcium channel pathway in isolated rat thoracic aorta. Conclusion: The study demonstrates the beneficial effect of Haloxylon scoparium as an antihypertensive agent. Moreover, this plant exerts vasorelaxant activity via the blockade of Ca²⁺ channels.