Letters in Drug Design & Discovery - Volume 18, Issue 3, 2021

Background: Leukemia is a severe type of blood cancer that involves an abnormal proliferation of blood-forming cells. Its conventional treatment faces many challenges, including resistance, lack of specificity and high unwanted toxicity of drugs. Nano drug delivery systems help in overcoming these challenges by delivering the drug to the target site actively or passively. Solid lipid nanoparticles are gaining popularity because they reduce unwanted toxicity, are biocompatible, increase bioavailability and are versatile in terms of incorporated agents (hydrophilic as well as lipophilic drugs, genes, enzymes, etc.). Purpose: The aim of this review is to discuss recent advancements in anti-leukemic therapy utilizing solid lipid nanoparticles (SLNs) as successful carriers in enhancing the efficiency of the treatment and bioavailability of the incorporated drug along with overcoming multidrug resistance. Methods: This review represents the existing literature on the applications of SLNs in anti-leukemic therapy. A qualitative literature review has been performed for this purpose. We performed keyword research in popular databases such as Google Scholar, Wiley, Elsevier, Scopus, Google patent and PubMed. Only articles published in English and from reputed journals from specific fields were considered. Benchmark studies having major importance from 2000 to 2020 were selected to follow the progress in the field across the globe. Results: This article improves the understanding of the role of SLNs in the treatment of leukemia. Traditional anti-leukemic therapy involves many challenges, including resistance, lack of specificity and high unwanted toxicity of drugs. SLNs are emerging as a better alternative to conventional delivery systems as they can reduce unwanted toxicity, are biocompatible, and can provide active as well as passive molecular targeting. Conclusion: SLNs provide several advantages in drug delivery for leukemia, including enhancement of efficiency and bioavailability and reduction of toxicity by virtue of their small size, lipid core, non-dependency on organic solvents and versatility in terms of incorporated drugs.

Substituted tetralones have played a substantial role in organic synthesis due to their strong reactivity and suitability as a starting material for a range of synthetic heterocyclic compounds, pharmaceuticals along with biological activities as well as precursors of many natural products and their derivatives. Many α-tetralone derivatives are building blocks that have been used in the synthesis of therapeutically functional compounds like some antibiotics, antidepressants, acetylcholinesterase inhibitors effective for treating Alzheimer’s disease and alkaloids possessing antitumor activity. In this review, there has been an attempt to explore the small molecule library having an α-tetralone scaffold along with their diverse biological activities. Structural features of α- tetralone derivatives responsible for potential therapeutic applications are also described.

Background: The liver is the second largest organ inside the human body. It can be damaged by several toxic molecules and medicinal agents taken in overdoses. Indeed, there are some oils obtained from different herbs that can be used to protect the liver injury. Objective: This review aims to give details on some oils that have been tested for their hepatoprotective effect. Methods: We reviewed 79 articles published between 1980 and 2019 in English language using three databases Sciencedirect, Web of Science and PubMed. So, we have used the keywords related to hepatoprotective activity: Hepatoprotective, liver disease, plant and oil and we have classified the plants in alphabetical order as a list containing their scientific and family names, as well as the experimental assay and the results obtained from these studies. Results: As a result, we have described 18 species belonging to 18 families: Altingiaceae, Apiaceae, Arecaceae, Asteraceae, Cactaceae, Caryocaraceae, Cucurbitaceae, Lauraceae, Leguminoseae, Malvaceae, Moringaceae, Myrtaceae, Oleaceae, Pinaceae, Ranunculaceae, Rosaceae, Theaceae and Vitaceae. Among the most common fatty acids present in hepatoprotective oils are palmitic acid, linoleic acid, oleic acid and stearic acid. Conclusion: These oils have shown beneficial properties regarding the hepatoprotective activity.

Background: A number of synthetic scaffolds, along with natural products, have been identified as potent antioxidants. The present study deals with the evaluation of varyingly substituted, medicinally distinct class of compounds “chalcones and bis-chalcones” for their antioxidant potential. Methods: In vitro radical scavenging activities were performed on a series of synthetic chalcones 1- 13 and bis-chalcones 14-18. Results: All molecules 1-18 revealed a pronounced 2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2´- azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radicals scavenging potential in the ranges of IC50s = 0.58 ± 0.14 - 1.72 ± 0.03 and 0.49 ± 0.3 - 1.48 ± 0.06 μM, respectively. Ascorbic acid (IC50s = 0.5 ± 0.1 and 0.46 ± 0.17 μM for DPPH and ABTS, respectively) was used as a standard radical scavenger. Conclusion: Structure-activity relationship (SAR) revealed an active participation of various groups, including -SMe and -OMe in scavenging activity.

Background: There are several reports on the anti-cancer property of zerumbone, such as in breast, cervical and ovarian cancer. But the investigation of the actual protein target has been the least concerned and there are few reports on the inhibitory effect of zerumbone against specific cancer-causing proteins and enzymes. Therefore, further investigation is required at a much deeper molecular level. Objective: This study aimed to determine the anti-proliferative activity of Zerumbone against cervical cancer cell and assess its TNF-α enzyme inhibitory action. Methods: The investigation emphasized the anti-cancer activity of zerumbone against HeLa cells and its subsequent TNF-α assay. Furthermore, computational studies on Zerumbone as an inhibitor of TNF-α were carried out using computational techniques such as docking and MD simulations. Results and Discussion: From the molecular docking analysis, it was observed and substantiated that the α,β-Unsaturated carbonyl scaffold is the main driving force for anti-cancer activity of zerumbone and inhibition of TNF-α. Conclusion: Zerumbone might be a potent anti-cancer agent targeting the HeLa cancer cell lines and inhibiting the TNF-α enzyme.

Background: The aim of this study was to synthesize new mannich bases and conazol derivatives with biological activity by the microwave-assisted method. Introduction: 1,2,4-Triazole-3-one (3) acquired from tryptamine was transformed to the corresponding carbox(thio)amides (6a-c) via several steps. Compounds 6a-c were refluxed with sodium hydroxide to yield 1,2,4-triazole derivatives (7a-c). Compounds 3 and 7a-c on treatment with different heterocyclic secondary amines in an ambiance with formaldehyde afforded the mannich bases 8-15 having diverse pharmacophore units with biologically active sites. The reaction of compound 3 and 2-bromo-1-(4-chlorophenyl) ethanone in the presence of sodium ethoxide gave the corresponding product 2-substituted-1,2,4-triazole-3-one, 16, which was reduced to 1,2,4-triazoles (17). Synthesis of compounds 18, 19, and 20 was carried out starting from compounds 17 with 4-chlorobenzyl chloride (for 18), 2,4-dichlorobenzyl chloride (for 19), and 2,6-dichlorobenzyl chloride (for 20). Methods: The conventional technique was utilized for the synthesis of compounds, 3-7, and microwave- assisted technique for the compounds, 8-20. That is, green chemistry techniques were applied during these reactions. The structures of molecules were elucidated on the foundation of ¹H NMR, ¹³C NMR, FT-IR, EI-MS methods, and elemental analysis. Novel synthesized molecules were investigated for their antimicrobial activity using MIC (minimum inhibitory concentration) method. Results: Aminoalkylation of triazole derivatives 3 and 7a-c with fluoroquinolones such as ciprofloxacin and norfloxacin provided an enhancement to the bioactivity of mannich bases 8-11 against the tested microorganisms. The MIC values ranged between <0.24 and 3.9 μg/mL. Moreover, molecules 10 and 11 exhibited more effects on M. smegmatis than the other compounds by the MIC values of <1 μg/mL. They have shown very good antituberculosis activity. Conclusion: Most of the synthesized structures were observed to have excellent antimicrobial activity against most microorganisms taken into account. These molecules have better activity than the standard drug ampicillin and streptomycin.

Background: Malaria is a deadly and infectious disease responsible for millions of death worldwide, mostly in the African region. The malaria parasite has developed resistance to the currently used antimalarial drugs, and it has urged researchers to develop new strategies to overcome this challenge by designing different classes of antimalarials. Objectives: A class of hybrid compounds containing 4-aminosalicylic acid moiety was prepared via esterification and amidation reactions and characterized using FTIR, NMR and LC-MS. In vitro antiplasmodial evaluation was performed against the asexual NF54 strain of P. falciparum parasites. Methods: In this research, known 4-aminoquinoline derivatives were hybridized with 4- aminosalicylic acid to afford hybrid compounds via esterification and amidation reactions. 4- aminosalicylic acid, a dihydrofolate compound inhibits DNA synthesis in the folate pathway and is a potential pharmacophore for the development of antimalarials. Results: The LC-MS, FTIR, and NMR analysis confirmed the successful synthesis of the compounds. The compounds were obtained in yields in the range of 63-80%. The hybrid compounds displayed significant antimalarial activity when compared to 4-aminosalicylic acid, which exhibited poor antimalarial activity. The IC50 value of the most potent hybrid compound, 9 was 9.54±0.57 nm. Conclusion: 4-aminosalicylic has different functionalities, which can be used for hybridization with a wide range of compounds. It is a potential pharmacophore that can be utilized for the design of potent antimalarial drugs. It was found to be a good potentiating agent when hybridized with 4- aminoquinoline derivatives suggesting that they can be utilized for the synthesis of a new class of antimalarials.

Background: Structurally diverse organic compounds and available drugs were screened against urease and carbonic anhydrase II in a formulation acceptable for high-throughput screening. Objective: The study was conducted to find out potential inhibitors of urease and carbonic anhydrase II. Methods: Quantification of the possible HITs was carried out by determining their IC50 values. Results: The results of several screened compounds, including derivatives of oxadiazole, coumarins, chromane-2, 4-diones and metal complexes of cysteine-omeprazole showed promising inhibitory activities with IC50 ranging from 47 μM to 412 μM against the urease. The interactions of active compounds with active sites of enzymes were investigated through molecular docking studies which revealed that (R)-1-(4-amino-4-(5-(thiophen-2-yl)-1,3,4-oxadiazol-2-yl) butyl) guanidine possessing IC50 of 47 μM interacts with one of the nickel metal atoms of urease besides further interactions as predictable hydrogen bonds with KCX490, Asp633, His492, His407 and His409 along with Ala440 and 636. Bi-ligand metal complexes of 4-aminoantipyrine based Schiff bases showed activation of urease with AC50 ranging from 68 μM to 112 μM. Almost 21 compounds with varying functional groups including pyrimidines, oxadiazoles, imidazoles, hydrazides and tin based compounds were active carbonic anhydrase II inhibitors presenting 98 μM to 390 μM IC50 values. Several N-substituted sulfonamide derivatives were inactive against carbonic anhydrase II. Conclusion: Among all the screened compounds, the highly active inhibitor of carbonic anhydrase II was (4-(3-hydroxyphenyl)-6-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl) methanone with IC50 of 98.0 μM. This particular compound showed metallic interaction with Zn ion of carbonic anhydrase II through the hydroxyl group of the phenyl ring.