Design, Synthesis and Antiplasmodial Evaluation of Sulfoximine-triazole Hybrids as Potential Antimalarial Prototypes

Background:Malaria, caused by the deadly Plasmodium falciparum strain, claims the lives of millions of people annually. The emergence of drug-resistant strains of P. falciparum to the artemisinin-based combination therapy (ACT), the last line of defense against malaria, is worrisome and urges for the development of new chemo-types with a new mode of action. In the search of new antimalarial agents, hybrids of triazoles and other known antimalarial drugs have been reported to possess better activity than either of the parent compounds administered individually. Despite their better activity, no hybrid antimalarial drugs have been developed so far.Objective:In the hope of developing new antimalarial prototypes, we propose the design, synthesis and antimalarial evaluation of novel sulfoximine-triazole hybrids owing to their interesting biological and physiological properties.Methods:The sulfoximine part of the hybrid will be synthesized via imidation of the corresponding sulfoxide. Propargylation of the NH moiety of the sulfoximine followed by copper-catalyzed click chemistry with benzyl azide was envisaged to provide the target sulfoximine-triazole hybrids.Results:Five novel sulfoximine-triazole hybrids possessing various substituents on the sulfoximine moiety have been successfully synthesized and evaluated for their antiplasmodial and cytotoxicity activities. The results revealed that the co-presence of the sulfoximine and triazole moieties along with a lipophilic alkyl substituent on the sulfur atom impart significant activity.Conclusion:Sulfoximine-triazole hybrids could be used as a prototype for the synthesis of new derivatives with better antiplasmodial activities.

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Sontochin as a Guide to the Development of Drugs against Chloroquine-Resistant Malaria

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00100-12 ◽

2012 ◽

Vol 56 (7) ◽

pp. 3475-3480 ◽

Cited By ~ 10

Author(s):

Sovitj Pou ◽

Rolf W. Winter ◽

Aaron Nilsen ◽

Jane Xu Kelly ◽

Yuexin Li ◽

...

Keyword(s):

Multidrug Resistant ◽

Plasmodium Yoelii ◽

Significant Activity ◽

Drug Resistant ◽

Content Type ◽

Resistant Strains ◽

Drug Resistant Strains ◽

Derivatives Of

ABSTRACTSontochin was the original chloroquine replacement drug, arising from research by Hans Andersag 2 years after chloroquine (known as “resochin” at the time) had been shelved due to the mistaken perception that it was too toxic for human use. We were surprised to find that sontochin, i.e., 3-methyl-chloroquine, retains significant activity against chloroquine-resistant strains ofPlasmodium falciparum in vitro. We prepared derivatives of sontochin, “pharmachins,” with alkyl or aryl substituents at the 3 position and with alterations to the 4-position side chain to enhance activity against drug-resistant strains. Modified with an aryl substituent in the 3 position of the 7-chloro-quinoline ring, Pharmachin 203 (PH-203) exhibits low-nanomolar 50% inhibitory concentrations (IC50s) against drug-sensitive and multidrug-resistant strains andin vivoefficacy against patent infections ofPlasmodium yoeliiin mice that is superior to chloroquine. Our findings suggest that novel 3-position aryl pharmachin derivatives have the potential for use in treating drug resistant malaria.

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Design, synthesis, and evaluation of novel diphenyl ether derivatives against drug-susceptible and drug-resistant strains of Mycobacterium tuberculosis

Chemical Biology & Drug Design ◽

10.1111/cbdd.13379 ◽

2018 ◽

Vol 93 (1) ◽

pp. 60-66 ◽

Cited By ~ 5

Author(s):

Sidhartha S. Kar ◽

Varadaraj G. Bhat ◽

Vishnu P. Shenoy ◽

Indira Bairy ◽

G. Gautham Shenoy

Keyword(s):

Mycobacterium Tuberculosis ◽

Diphenyl Ether ◽

Drug Resistant ◽

Design Synthesis ◽

Resistant Strains ◽

Drug Resistant Strains

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Design, Synthesis, Antimalarial Activity and Docking Study of 7-Chloro-4- (2-(substituted benzylidene)hydrazineyl)quinolines

Medicinal Chemistry ◽

10.2174/1573406415666190806154722 ◽

2020 ◽

Vol 16 (7) ◽

pp. 928-937 ◽

Cited By ~ 1

Author(s):

Jahnabi Kalita ◽

Dipak Chetia ◽

Mithun Rudrapal

Keyword(s):

Antimalarial Drug ◽

Disease Burden ◽

Antimalarial Activity ◽

Docking Study ◽

Molecular Scaffold ◽

Design Synthesis ◽

Antimalarial Agents ◽

Drug Molecules ◽

Resistant Strains

Background: Malaria is a growing infectious disease burden due to the increasing emergence of resistant strains of Plasmodium falciparum. Because of the limited therapeutic efficacy of available antimalarial drugs, the development of potent antimalarial drug agents is therefore an urgent requirement to fight against resistant malaria. Objective: The objective of this work was to develop novel quinoline-baed antimalarial agents that would be active against resistant P. falciparum malaria. Methods: Some 7-chloro-4-(2-(substituted benzylidene)hydrazineyl)quinolines were synthesized for the evaluation of their potential as possible antimalarial agents, particularly against resistant malaria. The antimalarial activity of synthesized compounds was evaluated in vitro against bloodstage parasites of P. falciparum. Further, molecular docking and drug-likeness including ADMET (Absorption, Distribution, Metabolism, Elimination and Toxicity) studies were also carried out using in silico tools. Results: Results reveal the in vitro antimalarial activity of synthesized 7-chloro-4-(2-(substituted benzylidene)hydrazineyl)quinolines against P. falciparum. The docking study investigates the antimalarial effectiveness of synthesized quinolines as novel plasmepsin 2 inhibitors. Drug-likeness prediction exhibits acceptable drug-likeness and ADMET properties. Conclusion: Based upon our findings, it is concluded that the molecular scaffold of 7-chloro-4-(2- (substituted benzylidene)hydrazineyl)quinolines may be used as a lead structure for further modifications in the search of more potent antimalarial drug molecules.

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Overview of Antiretroviral Agents in 2005

Journal of Pharmacy Practice ◽

10.1177/0897190005278612 ◽

2005 ◽

Vol 18 (4) ◽

pp. 228-246 ◽

Cited By ~ 2

Author(s):

Anela Stanic ◽

Tulip K. Schneider

Keyword(s):

Protease Inhibitors ◽

Transcriptase Inhibitor ◽

Fixed Dose ◽

Antiretroviral Agents ◽

Entry Inhibitors ◽

Fusion Inhibitors ◽

Resistant Strains ◽

Atazanavir Sulfate ◽

Reverse Transcriptase Inhibitor ◽

Drug Resistant Strains

To date, 25 antiretroviral agents (including fixed-dose combinations) have gained approval by the Food and Drug Administration and are currently available on the market for the treatment of HIV-1 infection. New protease inhibitors, atazanavir sulfate (Reyataz) and fosamprenavir (Lexiva), were licensed, in addition to the nucleoside analogue reverse transcriptase inhibitor (NRTI) emtricitabine (Emtriva) and 2 fixed-dose NRTI combinations, emtricitabine/tenofovir disoproxil fumarate (Truvada) and lamivudine/abacavir (Epzicom). These newly licensed antiretroviral agents allow for lower pill burden and dosing schedule simplification, and some agents such as atazanavir sulfate are associated with improved lipid profile in comparison to other currently marketed protease inhibitors. In addition, a new class of anti-retroviral agents, entry inhibitors, of which a subclass exists called fusion inhibitors with its representative member, enfuvirtide (Fuzeon), which is currently the only available drug in its class, was marketed almost 2 years ago. Despite a remarkable progress in the treatment of HIV infection noted during the past decade, significant challenges to therapy such as tolerability issues and emergence of drug-resistant strains remain. Therefore, new antiretroviral drug development has focused on a design of drugs that work against the resistant strains of HIV and/or have a novel mechanism of action.

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Design, Synthesis and Anticandidal Evaluation of Indazole and Pyrazole Derivatives

Pharmaceuticals ◽

10.3390/ph14030176 ◽

2021 ◽

Vol 14 (3) ◽

pp. 176

Author(s):

Karen Rodríguez-Villar ◽

Alicia Hernández-Campos ◽

Lilián Yépez-Mulia ◽

Teresita del Rosario Sainz-Espuñes ◽

Olivia Soria-Arteche ◽

...

Keyword(s):

Bloodstream Infections ◽

Antifungal Drugs ◽

Pyrazole Derivatives ◽

Design Synthesis ◽

Bioisosteric Replacement ◽

Current Therapies ◽

Anticandidal Activity ◽

Resistant Strains ◽

A Priority

Candidiasis, caused by yeasts of the genus Candida, is the second cause of superficial and mucosal infections and the fourth cause of bloodstream infections. Although some antifungal drugs to treat candidiasis are available, resistant strains to current therapies are emerging. Therefore, the search for new candicidal compounds is certainly a priority. In this regard, a series of indazole and pyrazole derivatives were designed in this work, employing bioisosteric replacement, homologation, and molecular simplification as new anticandidal agents. Compounds were synthesized and evaluated against C. albicans, C. glabrata, and C. tropicalis strains. The series of 3-phenyl-1H-indazole moiety (10a–i) demonstrated to have the best broad anticandidal activity. Particularly, compound 10g, with N,N-diethylcarboxamide substituent, was the most active against C. albicans and both miconazole susceptible and resistant C. glabrata species. Therefore, the 3-phenyl-1H-indazole scaffold represents an opportunity for the development of new anticandidal agents with a new chemotype.

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