Mini Reviews in Medicinal Chemistry - Volume 21, Issue 19, 2021

Cardiovascular diseases (CVD) are known to be the world's leading cause of death and different factors are known to increase the risk of death, including aging, mainly due to increased oxidative stress and inflammation observed in older people. Acute myocardial infarctions and cerebrovascular accidents belong to CVD, and are the ones that cause the most deaths and disabilities, where greater platelet activation plays an important role in pathophysiology. These diseases are more prevalent in older people, which have a clear relationship with increased platelet function and are strongly related to aging. Platelet function is affected by diet, which varies in its requirements and characteristics according to age. Coffee belongs to the family of diet elements that can alter platelet function and an increase in coffee consumption with advancing age, and a U-shaped correlation with the risk of CVD have been reported. However, the effect of coffee consumption and its bioactive compounds on platelet function and aging presents controversial evidence, and therefore, a complex effect is not fully elucidated in the cardiovascular system. This review focuses on the relationship between coffee consumption (and its constituent bioactive compounds), and platelet function, and aging.

As winter is approaching us, the possibility of respiratory tract infection is rising in the current scenario due to the lack of Covid-19 prophylaxis. So no one could be safe until everyone is safe. Researchers are looking for the vaccine to remove the need for social distancing, mask-wearing, and social gathering worldwide. We cannot say about the vaccine's effectiveness if the vaccine is available. Several drugs are being tested to save people's life from the pandemic; azithromycin is one of them. This work is a review article with the updated findings of azithromycin in the context of COVID-19. The option of azithromycin regarding COVID-19 is justified by its anti-inflammatory, immunomodulatory, and anti-fibrotic effects and their pharmacokinetic properties, leading to effective concentrations in the target tissue. Azithromycin tends to be an effective candidate for SARS-CoV-2 replication inhibition that blocks the initial stage of the viral life cycle. Clinical trials at a preliminary scale and final stage show the significant results of azithromycin in supportive care therapy. Azithromycin was an early candidate for the medication of Covid-19 with or without hydroxychloroquine. It is exercised mainly as an outpatient antibiotic in COVID-19. In summing up, any primary anti-viral and antibiotic treatment is not the only possibility of fighting COVID-19 pharmacologically. It will be an injustice to those who require broader spectrum antibiotics if we do not use azithromycin. So significant research priority is needed to determine whether azithromycin is useful in the treatment of COVID-19.

1, 2, 4-Triazine derivatives have received much attention due to their multifunctional nature, especially in diverse pharmacological properties as well as a key fragment in many drug candidates. Introduction of a vicinal 5, 6-diaryl/heteroaryl moiety on the 1, 2, 4-triazine ring has attracted plentiful attention in the field of medicinal chemistry. 5, 6-Diaryl/heteroaryl-3-substituted-1, 2, 4- triazine is a prominent scaffold in many drug candidates, which has shown a wide range of pharmacological activities such as anti-diabetic, antifungal, anti-inflammatory, anticancer, anti-HIV, neuroprotective, anticonvulsant, anti-Alzheimer, anti-Parkinson, and antioxidant. In this review, we have discussed synthesis, various pharmacological activities of 5, 6-diaryl/heteroaryl-3-substituted-1, 2, 4- triazines, their structure-activity relationship (SAR), pharmacophoric elements, and their mechanism of action reported in the published articles during 2000-2019. Evaluation of compounds by PAINS filtering tool was accomplished and showed that this versatile structure could be considered as a privileged structure. Compilation of the biological data confirmed that position 3 of the 1,2,4-triazine is a key location to determine the affinity and selectivity of the 5,6-diaryl/heteroaryl-3-substituted-1, 2, 4- triazines towards different biologic targets. Specific geometrical and thermodynamic characters of this motif have prompted it as a frequent hitter.

The carbazole skeleton, a key structural motif occurring naturally or chemically synthesized, showed various biological activities. Molecular hybridization based on the combination of two or more bioactive pharmacophores has been an important tool to convert the potent structural leads to form new hybrid compounds with improved biological activity. In recent years, modifications/ substitutions of the carbazole motif at C-3, C-6, and N-9 positions have been carried to develop novel carbazole-based potential anticancer agents in the therapy of cancer. In the last fifteen years, several compounds based on carbazole core integrated into pharmacologically active molecular hybrid having active pharmacophore such as1,3,4-thiadiazole, thiazole, guanidine, sulfonamides, glyoxamides, imidazoles, phenanthrenes, rhodamines, chalcones, imidazopyridine, platinum, 2-H-chromen- 2-one, hydrazones, piperazines, isoxazole-thiadiazole, pyrazoles, etc. have been synthesized showing anticancer profile at sub-micromolar to nano-molar concentrations. We have thoroughly reviewed the design, progress, and development of C-3, C-6, and N-9 positions substituted carbazole derivatives integrated with various medicinally active pharmacophore as potential anticancer agents evaluated against various cancer cell lines. Additionally, the anticancer mechanism and in vivo activity of the reported compounds have been discussed. This study will support in designing of new pharmacophore that can be linked to the carbazole motif for the development of new, potent, and target-specific anticancer drugs with improved pharmacokinetics and minimal side effects.

Rheumatoid Arthritis (RA) is a chronic inflammatory disease characterized by infiltration of inflammatory cells, synovial hyperplasia, pannus formation and bone destruction. RA is associated with high incidence of disability worldwide. Although several anti-RA agents are available in the market, clinical use of these drugs is limited due to their severe side effects. Several studies are currently exploring new anti-rheumatic drugs which are more effective and have fewer side effects. Notably, natural products with anti-RA effect have been identified and studies have reported the underlying molecular mechanisms of action of the novel and known compounds. This review explored naturally occurring known and novel compounds that have anti-RA activity. Further, the compounds are classified based on their molecular mechanisms of action as anti-RA agents. In addition, the safety of compounds from natural sources is compared with that of conventional drugs. In addition, clinical trials for anti-RA compounds isolated from natural plant sources were summarized in this manuscript.

Picrorhiza kurroa Royle ex Benth. (Family: Plantaginaceae) is a well-recognized Ayurvedic herb. It is commonly called “Kutki” or “Kurro” and ‘Indian gentian’. Iridoid glycosides are the plant’s bioactive constituents accountable for the bitter taste and medicinal properties of the plant. The iridoid glycosides such as picrosides and other active metabolites of the plant exhibit many pharmacological activities like hepatoprotective, antioxidant, anti-inflammatory, anticancer, immunomodulator, anti-ulcerative colitis, antimicrobial, etc. This review aims to provide updated information on the ethnobotany, synthetic phytochemistry, pharmacological potential, safety and toxicology of P. kurroa and its active metabolites. Indiscriminate exploitation, ecological destruction of natural habitats, slower plant growth and unawareness regarding cultivation and uprooting of plants have brought kutki an endangered status. Therefore, various techniques used for the conservation and production of bioactive metabolites from P. kurroa have also been reported. Information on the plant has been collected from Science Direct, Google Scholar, PubMed, Scopus using ‘Picrorhiza kurroa’, ‘Picroside-‘, ‘Picroside-II’, ‘Picroliv’, ‘Immunomodulator’ keywords. All studies on ethnobotany, phytochemistry and pharmacology of plant from 2010- 2020 were comprised in this review article. The possible directions for future research have also been outlined briefly in this review article.

Coumarins are found in higher plants like Rutaceae and Umbelliferae and essential oils of cinnamon bark, cassia leaf, and lavender oil. Coumarin compounds show different biological properties, viz antimicrobial, antibacterial, antifungal, antioxidant, antitumor, anti-HIV, antihypertension, anticoagulant, anticancer, antiviral, anti-inflammatory, analgesics, antidiabetic, anti-depressive, and other bioactive properties. Coumarin and its derivatives possess anticancer activity against different types of cancers such as prostate, renal, breast, laryngeal, lung, colon, CNS, leukemia, malignant melanoma. In this review, current developments of coumarin-based anticancer agents viz simple coumarin, furanocoumarin, pyranocoumarin, pyrone-substituted coumarin, and their important derivatives have been discussed. The coumarin-triazole, coumarin-chalcone, coumarin-thiosemicarbazone derivatives, and coumarin-metal complexes have been found more potent than coumarin. Hence, further study and structural improvement on coumarin and its derivatives may lead to the design and development of more potent anticancer agents.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Its pathogenesis is closely related to insulin resistance, obesity, type 2 diabetes, and hyperlipidemia. Due to the complex pathogenesis, there are no specific medications for treating NAFLD. The most effective way to treat NAFLD is to lose weight through diet intervention and exercise, but a large number of in vitro and in vivo experiments have confirmed that a variety of natural drugs can interfere with NAFLD through many mechanisms, and the curative effect is remarkable. This paper reviews the action mechanism of crude extracts of medicinal plants (Polygonum multiflorum, Artemisia annua leaves, and Artemisia annua leaves) and natural products such as berberine (BBR), curcumin, betulinic acid (BA), ginsenoside Rg1 (G-rg1), and silybin on NAFLD, which aims to provide useful information for further research and development of new drugs to improve the cure rate of non-alcoholic fatty liver.

Effective treatment of tuberculosis has been hampered by the emergence of drug-resistant strains of Mycobacterium therapeutic facilities tuberculosis. With the global resurgence of tuberculosis with the development of multidrug-resistant cases, there is a call for the development of new drugs to combat these diseases. Throughout history, natural products have afforded a rich source of compounds that have found many applications in the fields of medicine, pharmacy and biology, and continued to play a significant role in the drug discovery and development process. This review article depicts the various potential plant extracts as well as plant derived phytoconstituents against the H37rv, the most persistent strains of Mycobacterium tuberculosis and its multidrug strains.

It is estimated that by 2040, Chronic Kidney Disease (CKD) will be the 5th main cause of global deaths. It has been suggested that hyperphosphatemia is among the main factors leading to the increased risk of death. This review focuses on potential and currently used Phosphate Binders (PB). Aluminum hydroxide is presently not recommended due to potential aluminum toxicity. Calciumcontaining phosphate binders (CCPB) can cause calcium overload, resulting in hypercalcemia and an increased risk of cardiovascular diseases. Magnesium and calcium complexes were suggested to be as effective as sevelamer in the reduction of serum phosphate, with the potential to slow down the process of calcification. However, limited studies have been conducted in this area. Although sevelamer seemed to have a positive influence on cardiovascular calcification and arterial stiffness, its influence on mortality was unclear. Sevelamer crystal accumulation in the Gastrointestinal tract (GI) can cause gastrointestinal bleeding. Lanthanum carbonate seemed to lower all-cause mortality and reduce the chance of hypercalcemia, even though a deposit in the GI tract was observed. Colestilan, like sevelamer, reduced LDL cholesterol. Sucroferric oxyhydroxide had a lower pill burden than other PBs and it seemed to reduce serum FGF-23. Ferric citrate improved parameters that are related to anemia but can cause iron overload. Bixalomer appeared to have fewer gastrointestinal side effects than sevelamer. Nano-lanthanum hydroxide and SBR759 may have an interesting future as PBs. In conclusion, the development of new PBs should also take into consideration their potential to function as protection modifiers.

Alzheimer's disease (AD), one of the progressive neurodegenerative disorders, is characterized by clinical features such as memory loss, acquired skill loss, apraxia, and interpersonal and social communication disorders. The AD hallmarks at the neuropathological level include intracellular neurofibrillary tangles constituted by the hyperphosphorylated tau protein as well as the senile extracellular plaques dominated by the amyloid-β (Aβ) deposits. At present, AD treatment that mainly targeted towards improving symptoms and effective drugs to delay or stop disease progression is lacking. Vaccines and antibody-based therapies are a type of natural, synthetic, and gene recombinant biological product that treat or prevent disease progression by stimulating specific or non-specific immune responses. Compared with traditional targeted drugs, vaccines and antibodybased therapies have better safety and effectiveness and can even maintain the expression and stability of Aβ and Tau proteins in patients for a long time. Logically, vaccines and antibody-based therapies are somewhat different from traditional drugs because these drugs can achieve the therapeutic effect of AD by activating immune cells and regulating the immune system of patients themselves, thereby clearing disease-related proteins and long-term survival. Complete cure is also observed in some patients after receiving the immunotherapy. Currently available vaccines and antibody-based therapies mainly target Aβ and phosphorylated tau proteins. There are 44 vaccines and antibodybased therapies for AD, among which nine drugs are discontinued, three drugs are inactive, eleven drugs are in clinical phase 1, twelve drugs are in clinical phase 2, and seven drugs are in clinical phase 3. Currently, no vaccines and antibody-based therapies have been approved for AD treatment. In this paper, we review and analyse the research progress of vaccines and antibody-based therapies that are used to treat AD.