Publications by authors named "Sebastian Anusha"

Design and synthesis of novel 4-carboxamidopyrido[3,2-b]pyridine derivatives as novel rigid analogues of sorafenib are reported herein. The target compounds showed potent antiproliferative activities against a panel of NCI-60 cancer cell lines as well as hepatocellular carcinoma cell line. Compounds 8g and 9f were among the most promising derivatives in terms of effectiveness and safety.

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The recent emergence of different SARS-CoV-2 variants creates an urgent need to develop more effective therapeutic agents to prevent COVID-19 outbreaks. Among SARS-CoV-2 essential proteases is papain-like protease (SARS-CoV-2 PLpro), which plays multiple roles in regulating SARS-CoV-2 viral spread and innate immunity such as deubiquitinating and deISG15ylating (interferon-induced gene 15) activities. Many studies are currently focused on targeting this protease to tackle SARS-CoV-2 infection.

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The development of robust and step-economic strategies to access structurally diverse drug-like compound collections remains a challenge. A distinct structural option that constitutes the core scaffold of many biologically significant molecules is the quinazolinone ring system. Several members of this family of privileged substructures have gained attention due to their diverse biological activities.

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Article Synopsis
  • The text describes a method for creating diverse chemical structures, which is important for discovering new drugs.
  • It introduces a metal-free process that combines two types of chemical reactions to produce specific scaffolds with precise stereochemistry.
  • The approach allows for the efficient construction of various molecular architectures from simple starting materials in a single step.
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The design, synthesis, and biological activities of a new series of pyrazole derivatives are reported. The target compounds 1a-1w were initially investigated against NCI-60 cancer cell lines. Compounds 1f, 1h, 1k, and 1v exerted the highest anti-proliferative activity over the studied panel of cancer cell lines.

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Article Synopsis
  • The complexity-to-diversity (CtD) strategy is a key method for converting complex natural products into a variety of skeletal structures, but its effectiveness is often limited by the compatibility of reactions with different functional groups.
  • Our research group has developed innovative stereodivergent strategies using indoloquinolizine analogues, resulting in the efficient and selective creation of various natural product-like compounds, including camptothecin-inspired analogues and unique ring systems.
  • These advancements in synthetic design enable a modular approach to producing diverse biologically relevant natural product analogues and offer a versatile platform for other late-stage transformations in natural product chemistry.
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The indolo[2,3-]quinolizines, canthines, and arborescidines natural products exhibit a wide range of bioactivities including anticancer, antiviral, antibacterial, and anti-inflammatory, among others. Therefore, the development of modular and efficient strategies to access the core scaffolds of these classes of natural products is a remarkable achievement. The Complexity-to-Diversity (CtD) strategy has become a powerful tool that transforms natural products into skeletal and stereochemical diversity.

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Nature represents a rich source of compounds used for the treatment of many diseases. Camptothecin (CPT), isolated from the bark of Camptotheca acuminata, is a cytotoxic alkaloid that attenuates cancer cell replication by inhibiting DNA topoisomerase 1. Despite its promising and wide spectrum antiproliferative activity, its use is limited due to low solubility, instability, acquired tumour cell resistance, and remarkable toxicity.

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The last two decades or so have witnessed an upsurge in defining the art of designing complex natural products and nature-inspired molecules. Throughout these decades, fundamental insights into stereocontrolled, step-economic and atom-economical synthesis principles were achieved by the numerous synthetic accomplishments particularly in diversity-oriented synthesis (DOS). This has empowered the visualization of the third dimension in synthetic design and thus has resulted in a dramatic increase with today's diversity-oriented synthesis (DOS) at the forefront enabling access to diverse scaffolds with a high degree of stereochemical and skeletal complexity.

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The design and synthesis of a quality compound library containing a small number of skeletally diverse scaffolds, whose members rapidly deliver new chemical probes active against multiple phenotypes, is paramount in drug discovery. In this context, an efficient one-pot strategy for the synthesis of a mini library of sp-enriched hexahydropyrido[2',1':2,3]imidazo[1,5-]quinolinium and hexahydrothiazolo[2',3':2,3]imidazo[1,5-]quinolinium architectures, is described. This new one-pot method features a combination of Sc(OTf)-catalyzed [4 + 1]-cycloaddition with aza-Michael addition reactions.

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Diversity-oriented synthesis (DOS) has become a powerful synthetic tool that facilitates the construction of nature-inspired and privileged chemical space, particularly for sp -rich non-flat scaffolds, which are needed for phenotypic screening campaigns. These diverse compound collections led to the discovery of novel chemotypes that can modulate the protein function in underrepresented biological space. In this context, starting material-driven DOS is one of the most important tools used to build diverse compound libraries with rich stereochemical and scaffold diversity.

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The development of efficient and modular synthetic methods for the synthesis of diverse collection of privileged substructures needed for a drug design and discovery campaign is highly desirable. Benzoxazepine and indolopyrazine ring systems form the core structures of distinct members of biologically significant molecules. Several members of these families have gained attention due to their broad biological activities, which depend on the type of ring-fusion and peripheral substitution patterns.

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Octahydroindolo[2,3-a]quinolizine ring system forms the basic framework comprised of more than 2000 distinct family members of natural products. Despite the potential applications of this privileged substructure in drug discovery, efficient, atom-economic and modular strategies for its assembly, is underdeveloped. Here we show a one-step build/couple/pair strategy that uniquely allows access to diverse octahydroindolo[2,3-a]quinolizine scaffolds with more than three contiguous chiral centers and broad distribution of molecular shapes via desymmetrization of the oxidative-dearomatization products of phenols.

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The epidermal growth factor receptor (EGFR) is a validated therapeutic target for triple-negative breast cancer (TNBC). In the present study, we synthesize novel adamantanyl-based thiadiazolyl pyrazoles by introducing the adamantane ring to thiazolopyrazoline. On the basis of loss of cell viability in TNBC cells, 4-(adamantan-1-yl)-2-(3-(2,4-dichlorophenyl)-5-phenyl-4,5-dihydro-1-pyrazol-1-yl)thiazole (APP) was identified as a lead compound.

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In this report, we describe the synthesis of 1-(Phthalazin-4-yl)-hydrazine using bronsted acidic ionic liquids and demonstrate their ability to inhibit asexual stage development of human malaria parasite, Plasmodium falciparum. Through computational studies, we short-listed chemical scaffolds with potential binding affinity to an essential parasite protein, dihydroorotate dehydrogenase (DHODH). Further, these compounds were synthesized in the lab and tested against P.

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Bcl homologs prominently contribute to apoptotic resistance in cancer cells and serve as molecular targets in treatment of various cancers. Herein, we report the synthesis of biphenyl-adamantane derivatives by a ligand free palladium on carbon based Suzuki reaction using diisopropylamine as a base for the coupling of adamantane based aryl chloride with a variety of aryl boronic acids. Among the biphenyl derivatives synthesized, compound 3'-(adamantan-1-yl)-4'-methoxy-[1,1'-biphenyl]-3-ol (AMB) displayed cytotoxic activity against hepatocellular carcinoma cell lines without significantly affecting the normal cell lines.

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In this work, we describe the 'green' synthesis of novel 6-(adamantan-1-yl)-2-substituted-imidazo[2,1-b][1,3,4]thiadiazoles (AITs) by ring formation reactions using 1-(adamantan-1-yl)-2-bromoethanone and 5-alkyl/aryl-2-amino1,3,4-thiadiazoles on a nano material base in ionic liquid media. Given the established activity of imidazothiadiazoles against M. tuberculosis, we next examined the anti-TB activity of AITs against the H37Rv strain using Alamar blue assay.

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Malaria parasites are currently gaining drug-resistance rapidly, across countries and continents. Hence, the discovery and development of novel chemical scaffolds, with superior antimalarial activity remain an important priority, for the developing world. Our report describes the development, characterization and evaluation of novel bepotastine-based sulphonamide antimalarials inhibiting asexual stage development of Plasmodium falciparum parasites in vitro.

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1,2,3-Triazole-based heterocycles have previously been shown to possess significant anticancer activity in various tumor models. In the present study, we attached a 1,2,3-triazole moiety to the third position of a 1,2-benzisoxazole heterocycle via copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) with various alkynes and established for the title compounds significant antiproliferative effect against human acute myeloid leukemia (AML) cells. Among the tested compounds, 3-(4-(4-phenoxyphenyl)-1H-1,2,3-triazol-1-yl)benzo[d]isoxazole (PTB) was found to be the most potent antiproliferative agent with an IC50 of 2 μM against MV4-11 cells using MTT assay.

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The classical antivenom therapy has appreciably reduced snakebite mortality rate and thus is the only savior drug available. Unfortunately, it considerably fails to shield the viper bite complications like hemorrhage, local tissue degradation and necrosis responsible for severe morbidity. Moreover, the therapy is also tagged with limitations including anaphylaxis, serum sickness and poor availability.

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