Medicinal Chemistry - Volume 19, Issue 4, 2023

Alzheimer’s Disease (AD) is a multifactorial incurable neurodegenerative disorder. It is characterized by a decline of cholinergic function in parallel with β-amyloid fibril deposition. Such an imbalance causes severe loss in memory and cognition, leading to behavioral disturbances, depression, and ultimately death. During the last decades, only a few approved drugs were launched onto the market with indications for treating initial and moderate stages of AD. To date, cholinesterase inhibitors (ChEI) are the mainstay line of treatment to ameliorate AD symptoms. Tacrine and Donepezil are the most commonly prescribed anti-dementia drugs, given their potent inhibitory effects. Therefore, many trials have focused on both drugs' structures to synthesize new anti-dementia agents. This paper discusses recent trends of new AD-treating anti-dementia agents focusing on Tacrine and Donepezil analogs and multifunctional hybrid ligands.

Benzothiazole is a bicyclic heterocyclic compound that contains benzene fused with 1, 3- thiazole ring. Several researches established the potential of benzothiazoles as important moiety in various adverse pharmacological conditions. Benzothiazole and its derivatives have been in use and marketed as anti-microbial, anti-inflammatory, anti-diabetic, anti-oxidant, anti-convulsant, antitumor, etc. The variations in pharmacological potentials of benzothiazole and its derivatives have been rational with their chemical structure. Nowadays, hybridization of two or more pharmacophores to synthesize a single molecule with potent pharmacological action is used. This helps to synergize pharmacological properties, make interaction possible with many targets, or minimize the adverse effects associated with them. Several synthetic approaches have been reported for benzothiazole and its derivatives. In this present review article, we focused on recently adopted synthetic approaches for the synthesis of the benzothiazole nucleus and its derivatives. The structure-activity relationship in relation to different pharmacological activities has also been highlighted to provide a good understanding to the researchers for future research on benzothiazoles.

SARS-CoV-2 was first discovered in Wuhan in late 2019 and has since spread over the world, resulting in the present epidemic. Because targeted therapeutics are unavailable, scientists have the opportunity to discover new drugs or vaccines to counter COVID-19, and therefore a number of synthetic bioactive compounds are now being tested in clinical studies. Due to its broad therapeutic spectrum and low adverse effects, medicinal herbs have been used as traditional healing medication in those countries for ages. Due to a lack of synthetic bioactive antiviral medications, pharmaceutical and alternative therapies have been developed using a variety of herbal compositions. Due to the widespread availability of herbal and dietary products worldwide, people frequently use them. Notably, the majority of Bangladeshi people continue to use a variety of natural plants and herbs to treat various types of diseases. This review article discusses how previous research has shown that some herbs in Bangladesh have immunomodulatory and antiviral effects and how their active ingredients have been gathered. Even though FDA-approved medications and vaccines are available for the treatment of COVID-19, the purpose is to encourage the use of herbal medicine as immunomodulators and vaccine adjuvants for the treatment of COVID-19 prevention.

Background: Hyperuricemia is associated with several disease conditions, such as atherosclerosis, arthritis, kidney stones, and many others. Xanthine oxidase (XO) is an enzyme that catalyzes the conversion of xanthine to uric acid. Hence, XO is a major therapeutic drug target in the treatment of hyperuricemia and associated disorders. Objectives: The current study aimed to identify XO inhibitors based on quinazoline derivatives, with the potential to be used against gout and other hyperuricemia-associated diseases. Methods: In the current study, eighteen quinazoline derivatives 2-19 were synthesized and assessed for their in vitro xanthine Oxidase (XO) inhibitory activity. Furthermore, the most active compounds, 5 and 17, were subjected to kinetics studies, followed by computational docking. Human BJ fibroblast cells were used to measure the cytotoxicity of active compounds. Results: Compounds 4-6, 8, 10, 13, 15-17, and 19 were found active against XO, with an IC50 values between 33.688 to 362.173μM. The obtained results showed that compounds 5 and 17 possess a significant xanthine oxidase inhibitory activity. The kinetics and molecular docking studies suggested that compounds 5 (IC50 = 39.904 ± 0.21 μM) and 17 (IC50 = 33.688 ± 0.30 μM) bind in the allosteric site of XO and exhibit a non-competitive type of inhibition. The molecular docking studies also predicted that the NH group of the pyrimidine ring binds with Ser344 residues of XO. Furthermore, all active compounds were non-cytotoxic on the human BJ fibroblasts cell line. Conclusion: This study identifies a series of quinazoline compounds as xanthine oxidase inhibitors, with the potential to be further investigated.

Background: Cardiovascular disease is one of the leading causes of death. Atherosclerosis causes arterial constriction or obstruction, resulting in acute cardiovascular illness. Cholesteryl ester transfer protein (CETP) facilitates reverse cholesterol transport. It supports the transfer of cholesteryl ester from HDL to LDL and VLDL. Inhibition of CETP by drugs limits cardiovascular disease by decreasing LDL and increasing HDL. Objectives: In this study, fourteen trifluoromethyl substituted benzene sulfonamides 6a-6g and 7a-7g were prepared. Methods: The synthesized molecules were characterized using ¹H-NMR, ¹³C-NMR, IR and HR-MS. They were in vitro tested to estimate their CETP inhibitory activity. Results: In vitro biological evaluation showed that compounds 7d-7f had the highest inhibitory activity with 100% inhibition, while the inhibition observed by compounds 6a-6g, 7a-7c and 7g ranged from 2%-72% at 10 μM concentration. It was found that the addition of a fourth aromatic ring significantly improved the activity, which may be due to the hydrophobic nature of CETP. Also, the presence of ortho-chloro, meta-chloro and para-methyl substituents results in high inhibitory activity. Conclusion: The induced fit docking studies revealed that hydrophobic interaction guided ligand/ CETP binding interaction in addition to H-bond formation with Q199, R201, and H232. Furthermore, pharmacophore mapping demonstrated that this series satisfies the functionalities of the current CETP inhibitors.