Antimalarial Mannoxanes: Hybrid Antimalarial Drugs with Outstanding Oral Activity Profiles and A Potential Dual Mechanism of Action

Chadwick, James; Amewu, Richard K.; Martí, Francesc; Garah, Fatima El; Sharma, Raman; Berry, Neil G.; Stocks, Paul A.; Burrell‐Saward, Hollie; Wittlin, Sergio; Rottmann, Matthias; Brun, Reto; Taramelli, Donatella; Parapini, Silvia; Ward, Stephen A.; O’Neill, Paul M.

doi:10.1002/cmdc.201100196

Cited by 26 publications

(10 citation statements)

References 27 publications

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“…1 H NMR (500 MHz, CDCl 3 , δ): 7.46 (d, J = 9.3 Hz, 2H), 7.44 (d, J = 9.3 Hz, 2H), 7.37 (d, J = 8.6 Hz, 2H), 6.90 (d, J = 8.6 Hz, 2H), 4.71 (s, 1H); 13 C{ 1 H} NMR (125 MHz, CDCl 3 , δ): 155.4, 139.3, 133.0, 132.9, 129.0, 128.4, 128.1, 115.9. Spectral data are consistent with those previously reported …”

Section: Experimental and Computational Detailssupporting

confidence: 92%

“…Spectral data are consistent with those previously reported. 40 (4′-Chloro-[1,1′-biphenyl]-4-yl)methanol (14b). Product 14b was prepared according to the general procedure using 4-chlorophenyl trifluoromethanesulfonate (1, 70 μL, 0.4 mmol, 1 equiv), 4-(hydroxymethyl)phenylboronic acid (76.0 mg, 0.5 mmol, 1.25 equiv), KF (69.7 mg, 1.2 mmol, 3 equiv), 5 (7.5 mg, 0.012 mmol, 3 mol %), degassed H 2 O (50 μL, 2.76 mmol, 6.9 equiv), and THF (0.8 mL) followed by purification procedure A. Purification by flash column chromatography (R f = 0.3 in 20% EtOAc, 10% benzene, 70% hexanes) provided 14b as a white solid (52.9 mg, 60% yield).…”

Section: The Journal Of Organic Chemistrymentioning

confidence: 99%

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N-Heterocyclic Carbene Ligand-Controlled Chemodivergent Suzuki–Miyaura Cross Coupling

2019

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Two N-heterocyclic carbene (NHC) ligands provide orthogonal chemoselectivity during the Pd-catalyzed Suzuki-Miyaura (SM) cross coupling of chloroaryl triflates. The use of SIPr [SIPr = 1,3-bis(2,6-diisopropylphenyl)-4,5-dihydroimidazol-2-ylidene] leads to selective cross coupling at chloride, while the use of SIMes [SIMes = 1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene] provides selective coupling at triflate. With most chloroaryl triflates and arylboronic acids, ligand-controlled selectivity is high (≥10:1). The scope of this methodology is significantly more general than previously reported methods for selective SM coupling of chloroaryl triflates using phosphine ligands. Density functional theory (DFT) studies suggest that palladium's ligation state during oxidative addition is different with SIMes compared to SIPr. Ar OTf [Pd] SIPr [Pd] SIMes ArB(OH) 2 KF, r.t. ArB(OH) 2 KF, r.t. OTf Cl Ar Cl Ar OTf [Pd] SIPr [Pd] SIMes ArB(OH) 2 KF, r.t. ArB(OH) 2 KF, r.t.OTf Cl Ar Cl SIPr SIMes IPr IMes N Cl Pd Cl Cl SIPr 7 Cl NHC Pd tBu 3, NHC = SIPr 4, NHC = IPr 5, NHC = SIMes 6, NHC = IMes Me PMP OTf Cl

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Section: Experimental and Computational Detailssupporting

confidence: 92%

Section: The Journal Of Organic Chemistrymentioning

confidence: 99%

N-Heterocyclic Carbene Ligand-Controlled Chemodivergent Suzuki–Miyaura Cross Coupling

2019

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“…Thus, the combination of a tetraoxane and a phenolic Mannich base moiety afforded hybrids 216 called mannoxanes ( Fig. 40), which are active at low nanomolar concentrations and surpass the ability of artesunate, tetraoxane RKA 182 and a peroxide/amodiaquine combination to cure malaria in mice at 10 mg/kg [333]. Hybridization of artemisin with a phenolic Mannich base moiety led to candidates 217 (Fig.…”

Section: Antimalarial Activitymentioning

confidence: 99%

Mannich bases in medicinal chemistry and drug design

Roman¹

2015

European Journal of Medicinal Chemistry

281

110

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The biological activity of Mannich bases, a structurally heterogeneous class of chemical compounds that are generated from various substrates through the introduction of an aminomethyl function by means of the Mannich reaction, is surveyed, with emphasis on the relationship between structure and biological activity. The review covers extensively the literature reports that have disclosed Mannich bases as anticancer and cytotoxic agents, or compounds with potential antibacterial and antifungal activity in the last decade. The most relevant studies on the activity of Mannich bases as antimycobacterial agents, antimalarials, or antiviral candidates have been included as well. The review contains also a thorough coverage of anticonvulsant, anti-inflammatory, analgesic and antioxidant activities of Mannich bases. In addition, several minor biological activities of Mannich bases, such as their ability to regulate blood pressure or inhibit platelet aggregation, their antiparasitic and anti-ulcer effects, as well as their use as agents for the treatment of mental disorders have been presented. The review gives in the end a brief overview of the potential of Mannich bases as inhibitors of various enzymes or ligands for several receptors.

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“…A single hybrid molecule with dual modes of action may therefore be beneficial for the treatment of resistant malaria with high antimalarial efficacy and resistance-preventing action. Alternatively, hybrid compounds may exhibit a unique mechanism of action which is likely to be different from the candidate drugs against which malaria parasites have developed resistance 43–49. In hybrid endoperoxides, also known as chimeric peroxides, mostly quinoline and peroxide moieties are the contributing pharmacophoric groups.…”

Section: Endoperoxide Antimalarials: Structural Diversity and Bioactimentioning

confidence: 99%

Endoperoxide antimalarials: development, structural diversity and pharmacodynamic aspects with reference to 1,2,4-trioxane-based structural scaffold

Rudrapal¹,

Chetia²

2016

DDDT

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Malaria disease continues to be a major health problem worldwide due to the emergence of multidrug-resistant strains of Plasmodium falciparum. In recent days, artemisinin (ART)-based drugs and combination therapies remain the drugs of choice for resistant P. falciparum malaria. However, resistance to ART-based drugs has begun to appear in some parts of the world. Endoperoxide compounds (natural/semisynthetic/synthetic) representing a huge number of antimalarial agents possess a wide structural diversity with a desired antimalarial effectiveness against resistant P. falciparum malaria. The 1,2,4-trioxane ring system lacking the lactone ring that constitutes the most important endoperoxide structural scaffold is believed to be the key pharmacophoric moiety and is primarily responsible for the pharmacodynamic potential of endoperoxide-based antimalarials. Due to this reason, research into endoperoxide, particularly 1,2,4-trioxane-, 1,2,4-trioxolane- and 1,2,4,5-teraoxane-based scaffolds, has gained significant interest in recent years for developing antimalarial drugs against resistant malaria. In this paper, a comprehensive effort has been made to review the development of endoperoxide antimalarials from traditional antimalarial leads (natural/semisynthetic) and structural diversity of endoperoxide molecules derived from 1,2,4-trioxane-, 1,2,4-trioxolane- and 1,2,4,5-teraoxane-based structural scaffolds, including their chimeric (hybrid) molecules, which are newer and potent antimalarial agents.

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Antimalarial Mannoxanes: Hybrid Antimalarial Drugs with Outstanding Oral Activity Profiles and A Potential Dual Mechanism of Action

Cited by 26 publications

References 27 publications

N-Heterocyclic Carbene Ligand-Controlled Chemodivergent Suzuki–Miyaura Cross Coupling

N-Heterocyclic Carbene Ligand-Controlled Chemodivergent Suzuki–Miyaura Cross Coupling

Mannich bases in medicinal chemistry and drug design

Endoperoxide antimalarials: development, structural diversity and pharmacodynamic aspects with reference to 1,2,4-trioxane-based structural scaffold

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