Mini Reviews in Medicinal Chemistry - Volume 21, Issue 17, 2021

Curcuma longa has been mentioned in the Indian system of medicine for the management of a wide range of diseases. C. longa and its metabolites like curcumin, ar-turmerone, methylcurcumin, demethoxy-curcumin, and bisdemethoxycurcumin have also been reported to be beneficial in various types of cancer. Curcumin elicits anticancer properties chiefly by triggering apoptotic pathways in cancer cells. The properties are facilitated through diverse signaling pathways viz. pathways mediated by NF-kB, WNT/β-catenin pathway COX-2, LOX, STAT3, prostaglandin E2, phosphorylase kinase, VEGF, AKT, AP1, STAT3, PI3K, Akt, mTOR, ERK5, AP-1, TGF-b, PPARc, EBPa, NLRP3 inflammasome, p38MAPK, Nrf2, Notch-1, AMPK, TLR-4, etc. The present article highlights curcumin biosynthesis, phytochemistry and diverse molecular pathways involved in regulating several types of secondary messengers to exhibit anticancer activity in almost all the forms of cancer.

Erythroxylaceae is a family composed of four genera, with Erythroxylum being the only one represented in the Neotropical region. Chemical studies indicate the presence of alkaloids, terpenes, flavonoids, and phenolic compounds as main compounds. The incorporation of cytotoxic activity assays of natural products using cell cultures assists in the selection of potential chemotherapeutic agents. In this work, we describe a revision of the cytotoxicity evaluation studies performed with extracts or pure substances obtained from Erythroxylum species through an integrative review. We found studies that evaluated the cytotoxic activity of 21 species of Erythroxylum against 45 different cell lines. The analysis of the chemical composition of these species shows that the metabolites present in each species influence their cytotoxic potential, especially the presence of disubstituted tropane alkaloid species with the highest cytotoxic potential. MTT and Sulforrodamine B assays were the main in vitro tests used for the evaluation of the cytotoxic activities. From the total species, less than 10% of the Erythroxylum species have already been evaluated for cytotoxic activity. Four of them showed high cytotoxic activity according to the criteria of the NCI plant screening program. Thus, this genus represents a potential source of natural products with antitumor activity.

Background: Hyperlipidemia is characterized by high level of cholesterol and triglycerides in blood. Various classes of drugs like statins, fibrates, niacin etc. are used for treatment of hyperlipidaemia. Objective: Niacin, which is one of the beneficial anti-hyperlipidemic agents, helps decreasing LDL cholesterol by 20 to 40% and causes increase of HDL cholesterol by 20 to 35%. However cutaneous flushing, loss of glucose tolerance, liver toxicity are the reported side effects of niacin therapy responsible for decreased patient compliance. Very recently, the G protein coupled receptor (GPCR); GPR109A located on the adipocytes has been identified as the receptor for activation of niacin. Method: In-vitro studies have demonstrated that GPR109A receptor having high affinity for niacin. The present review attempts to provide a systematic presentation of the various chemical classes of compounds that have been reported as novel niacin receptor agonists including pyrazole-3-carboxylic acids, urea derivatives, anthranilic acids, biaryl anthranilides, tetrahydro anthranilic acid, xanthines, barbituric acid, bicyclic pyrazole carboxylic acids, pyrido pyrimidinones, pyrazolyl propionyl cyclohexenamides, pyrazole acids etc. Results: As the design of GPR109A receptor agonists offers a promising solution for treatment of dyslipidemia, this review will be beneficial for medicinal and drug discovery chemists to expediate the process of discovery of new class of anti-hyperlipidemic agent with favorable lipid lowering profile with increase in HDL levels. Conclusion: This review explains novel GPR109A receptor agonists for the treatment of dyslipidemia.

Virus, a sub-microscopic infectious agent that replicates only inside the living cells of a host, causes viral infection. Currently, the immediate imperative is to control the combat against novel coronavirus outbreak caused by the COVID-19 virus, which started in China and spread all over the world. The domain of travelling has emphasized COVID-19 virus prevention as a serious issue for the safety of human beings. The exponential rise in the number of corona patients is a matter of concern for governing bodies of various countries in spite of countless cooperative efforts put in by citizens, organizations and government. India is now among the top worst hit nation in terms of the spread of COVID-19 pandemic. The present article reviews various state-of-art medicinal approaches available that are presently used to control the spread of coronavirus pandemic.

Alzheimer's disease is a neurodegenerative disorder that results in progressive and irreversible central nervous system impairment, which has become one of the severe issues recently. The most successful approach of Alzheimer’s treatment is the administration of cholinesterase inhibitors to prevent the hydrolysis of acetylcholine and subsequently improve cholinergic postsynaptic transmission. This review highlights a class of heterocycles, namely xanthone, and its remarkable acetylcholinesterase inhibitory activities. Naturally occurring xanthones, including oxygenated, prenylated, pyrano, and glycosylated xanthones, exhibited promising inhibition effects towards acetylcholinesterase. Interestingly, synthetic xanthone derivatives with complex substituents such as alkyl, pyrrolidine, piperidine, and morpholine have shown greater acetylcholinesterase inhibition activities. The structure-activity relationship of xanthones revealed that the type and position of the substituent(s) attached to the xanthone moiety influenced acetylcholinesterase inhibition activities where hydrophobic moiety will lead to an improved activity by contributing to the π-π interactions, as well as the hydroxy substituent(s) by forming hydrogen-bond interactions. Thus, further studies, including quantitative structure-activity relationship, in vivo and clinical validation studies are crucial for the development of xanthones into novel anti-Alzheimer's disease drugs.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a novel coronavirus strain and the causative agent of COVID-19 was emerged in Wuhan, China, in December 2019 [1]. This pandemic situation and magnitude of suffering have led to global effort to find out effective measures for discovery of new specific drugs and vaccines to combat this deadly disease. In addition to many initiatives to develop vaccines for protective immunity against SARS-CoV-2, some of which are at various stages of clinical trials, researchers worldwide are currently using available conventional therapeutic drugs with the potential to combat the disease effectively in other viral infections and it is believed that these antiviral drugs could act as a promising immediate alternative. Remdesivir (RDV), a broad-spectrum anti-viral agent, initially developed for the treatment of Ebola virus (EBOV) and known to showed promising efficiency in in vitro and in vivo studies against SARS and MERS coronaviruses, is now being investigated against SARS-CoV-2. On May 1, 2020, The U.S. Food and Drug Administration (FDA) granted Emergency Use Authorization (EUA) for RDV to treat COVID- 19 patients [2]. A number of multicentre clinical trials are on-going to check the safety and efficacy of RDV for the treatment of COVID-19. Results of published double blind, and placebo-controlled trial on RDV against SARS-CoV-2, showed that RDV administration led to faster clinical improvement in severe COVID-19 patients compared to placebo. This review highlights the available knowledge about RDV as a therapeutic drug for coronaviruses and its preclinical and clinical trials against COVID-19.

Purpose: Alpha-hydroxy acids (AHAs) are one of the classes of hydroxy acids being beneficial for human health. The manuscript summarizes the biological properties of two popular members of AHAs, i.e., Mandelic Acid (MA) and Gallic Acid (GA), with particular emphasis on antimicrobial properties. Moreover, attempts to design new derivatives improving the natural properties of AHAs by using the chemical and physical approach are discussed. Methods: Antimicrobial properties of MA, an arylalkyl AHA containing phenyl group attached to α- carbon, and GA, an aromatic trihydroxybenzoic acid containing the phenolic ring and carboxylic acid functional group, and their derivatives against common human and plant pathogenic fungi have been reviewed. Results: The antimicrobial activity of MA and GA is a complex phenomenon strictly correlated with other properties exhibited by these acids, e.g., pro-oxidative activity and hydrophobicity. In most cases, the acids derivatives exhibited higher antimicrobial activity than the acids themselves. This is probably because of the higher lipophilicity of moiety that allows better penetration through the cell membrane. Conclusion: MA and GA present an excellent health-promoting tool and are valuable starting materials for the design of new compounds such as metal complexes with alkali, or alkali earth metals. The lipophilic, antimicrobial, and pro-oxidative properties act synergistically, supporting the pharmacological and therapeutic effect of acids and their derivatives.

Derivatives of monosaccharides and oligosaccharides play important roles in biological processes. Monosaccharides are the single carbohydrate building blocks, such as glucose, xylose, and fructose. Oligosaccharides are composed of 2-10 monosaccharides, including disaccharides and trisaccharides. Moreover, monosaccharides, oligosaccharides and their derivatives are vital molecules with various biological properties, including anticancer activity, antiviral activity, insecticidal activity, antimicrobial activity, and antioxidant activity. This review covers a survey of structural modifications, biological activities, and mechanisms of action of monosaccharides, oligosaccharides and their derivatives. Additionally, their structure-activity relationships are also concluded.

Aralia elata (Miq.) Seem. (Araliaceae), which is the key point of this review, is a precious wild vegetable that has served in the treatment of diabetes and rheumatoid arthritis in traditional folk medicine in East Asia (China, Japan, Korea, Russia). This review aims to overview the results of the current research related to Aralia elata (Miq.) Seem., with particular emphasis on chemical composition and biological activity. The existing research has been searched and summarized through the database, and it has been found that it has a certain therapeutic effecta on a variety of chronic diseases such as: malignant tumors, cardio-cerebrovascular disease, diabetes, and its complications, etc. Additionally, it is loved by people in East Asia due to its rich taste as a wild vegetable. In conclusion, it offers the possibility of developing innovative pharmacological drugs as well as healthy food. Thus, it is critical to prove its validity and clarify the exact action mechanisms that promote it as a pharmacological drug. This review is expected to provide direction for future research.

Heterocyclic compounds play a critical role in medicinal chemistry, and many available drugs contain heterocyclic rings. A six-membered heterocyclic compound, pyridine, showed various applications, including being an important solvent, reagent, and precursor in agrochemicals and pharmaceuticals. Due to the increase in drug resistance, there is an apparent medical need to develop new antiviral agents. Various derivatives of pyridine scaffold display broad biological activities such as anti-microbial, antiviral, antioxidant, anti-diabetic, anti-cancer, anti-malarial, analgesic, and antiinflammatory activities. Furthermore, they display psychopharmacological, antagonistic, anti-amoebic agents, and anti-thrombic activities. Due to the high importance of pyridine derivatives, in the present review, we tried to collect and classify many pyridine derivatives based on their structures from 2000 to 2020. Pyridine derivatives were classified into two general categories, including pyridine containing heterocycles and pyridine fused rings. The structure-activity relationship (SAR) and the action mechanism of derivatives were also investigated. According to the recent studies, these derivatives exhibited good antiviral activity against different types of viruses such as the human immunodeficiency viruses (HIV), the hepatitis C virus (HCV), the hepatitis B virus (HBV), respiratory syncytial virus (RSV), and cytomegalovirus (CMV). These derivatives inhibited viral application with different action mechanism such as RT inhibition, polymerase inhibition, inhibition of RNase H activity, inhibition of maturation, inhibition of the viral thymidine kinase, AAK1 (Adaptor-Associated Kinase 1) inhibition, GAK (Cyclin G-associated kinase) inhibition, inhibition of post-integrational event, inhibition of HDAC6, CCR5 antagonistic activity, DNA and RNA replication inhibition, gene expression inhibition, cellular NF-jB signaling pathway and neuraminidase (NA) inhibition, protein synthesis inhibition, and generally inhibition of viral replication cycle. This paper summarized the past and present results about the discovery of novel lead compounds with good antiviral activity. Studies exhibited that almost all of the evaluations were performed by way of in vitro testing. It is necessary to investigate in vivo and clinical testing for better evaluations in the future. We believe that pyridine derivatives can be used as promising antiviral agents and more broad investigations in this field need to be performed.

Vitamin-D deficiency is a global concern. Gene mutations in the vitamin D receptor’s (VDR) ligand binding domain (LBD) variously alter the ligand binding affinity, heterodimerization with retinoid X receptor (RXR) and inhibit coactivator interactions. These LBD mutations may result in partial or total hormone unresponsiveness. A plethora of evidence reports that selective long chain polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and arachidonic acid (AA) bind to the ligand-binding domain of VDR and lead to transcriptional activation. We, therefore, hypothesize that selective PUFAs would modulate the dynamics and kinetics of VDRs, irrespective of the deficiency of vitamin-D. The spatial arrangements of the selected PUFAs in VDR active site were examined by in-silico docking studies. The docking results revealed that PUFAs have fatty acid structure-specific binding affinity towards VDR. The calculated EPA, DHA & AA binding energies (Cdocker energy) were lesser compared to vitamin-D in wild type of VDR (PDB id: 2ZLC). Of note, the DHA has higher binding interactions to the mutated VDR (PDB id: 3VT7) when compared to the standard Vitamin-D. Molecular dynamic simulation was utilized to confirm the stability of potential compound binding of DHA with mutated VDR complex. These findings suggest the unique roles of PUFAs in VDR activation and may offer alternate strategy to circumvent vitamin-D deficiency.