Discovery of Antischistosomal Drug Leads Based on Tetraazamacrocyclic Derivatives and Their Metal Complexes

Khan, Madeeha; Keiser, Jennifer; Amoyaw, Prince N.-A.; Hossain, Mohammad Faisal; Vargas, Mireille; Le, Justin G.; Simpson, Natalie; Roewe, Kimberly D.; Freeman, TaRynn N. Carder; Hasley, Travis R.; Maples, Randall D.; Archibald, Stephen J.; Hubin, Timothy J.

doi:10.1128/aac.00778-16

Cited by 27 publications

(25 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The beneficial effect of the coordination of Fe 2+ and Mn 2+ to tetraazamacrocycles has been reported by Hubin et al [14,16] and Khan et al [15]. Our future research will investigate the antimicrobial activities of metal complexes supported by cyclam and cyclen ligands.…”

Section: Discussionmentioning

confidence: 56%

“…The detailed understanding of the virus entrance mechanism led to the development of novel cyclam-based antivirals [12]. Tetraazamacrocycles and their metal complexes have also been studied as antimalarial [13,14], antischistosomal [15], as well as antileishmanial drugs [16]. Furthermore, the latter compounds have been investigated as anticancer agents [17].…”

Section: Introductionmentioning

confidence: 99%

“…Compounds 6-10 were converted into the corresponding acetate salts (11)(12)(13)(14)(15) in high yields upon protonation of the two remaining NH groups of the macrocycles with acetic acid. The chloride and bromide salts (16)(17)(18)(19)(20)(21) were obtained by the addition of concentrated aqueous solutions of HCl and HBr to ethanolic solutions of compounds 6-10, respectively.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Investigations into the Structure/Antibacterial Activity Relationships of Cyclam and Cyclen Derivatives

Alves¹,

Portel

Sousa

et al. 2019

Antibiotics

View full text Add to dashboard Cite

A series of cyclam- and cyclen-derived salts are described in the present work; they were designed specifically to gain insights into their structure and antibacterial activity towards Staphylococcus aureus and Escherichia coli, used respectively, as Gram-positive and Gram-negative model organisms. The newly synthesized compounds are monosubstituted and trans-disubstituted tetraazamacrocycles that display benzyl, methylbenzyl, trifluoromethylbenzyl, or trifluoroethylbenzyl substituents appended on the nitrogen atoms of the macrocyclic ring. The results obtained show that the chemical nature, polarity, and substitution patterns of the benzyl groups, as well as the number of pendant arms, are critical parameters for the antibacterial activity of the cyclam-based salts. The most active compounds against both bacterial strains were the trans-disubstituted cyclam salts displaying CF3 groups in the para-position of the aromatic rings of the macrocyclic pendant arms. The analogous cyclen species presents a lower activity, revealing that the size of the macrocyclic backbone is an important requirement for the antibacterial activity of the tetraazamacrocycles. The nature of the anionic counterparts present on the salts was found to play a minor role in the antibacterial activity.

show abstract

Section: Discussionmentioning

confidence: 56%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Investigations into the Structure/Antibacterial Activity Relationships of Cyclam and Cyclen Derivatives

Alves¹,

Portel

Sousa

et al. 2019

Antibiotics

View full text Add to dashboard Cite

show abstract

“…A possible novel drug lead for schistosomiasis that is comparable to the standard PZQ drug was hence discovered in a Fe 2+ complex that exhibited activity in vivo. 61 iii. Praziquantel Praziquantel is the generic name for (2-cyclohexylcarbonyl)-1,2,3,6,7,11b-hexa-hydro-4Hpyrazino(2,1-α) isoquinoline-4-one, a bitter-tasting white crystalline powder created in the pyrazino-isoquinoline ring system, which was initially created for the development of a tranquilizer compound.…”

Section: B Tetraazamacrocyclic Derivatives and Their Metal Complexesmentioning

confidence: 99%

Bioorganometallic Compounds as Novel Drug Targets against Schistosomiasis in Sub-Saharan Africa: An alternative to Praziquantel?

2021

View full text Add to dashboard Cite

Human schistosomiasis is a disease that mostly plagues the destitute of various tropical and sub-tropical countries, particularly in sub-Saharan Africa and South America. It has significant effects on various health and economic-related matters. Globally, the burden of schistosomiasis has been controlled with a single chemotherapeutic drug, Praziquantel, which has recently demonstrated several clinical issues, including its inability to destroy juvenile schistosome worms and drug resistance because of its extensive use. The use of organometallic moieties in biological and medicinal chemistry has developed greatly and has led to their use in various anti-cancer and anti-infectious agents. The abundance of a range of organometallic compounds that can cause damage to the parasite has received tremendous feedback, with many already at clinical trials. The distinct redox biology of the schistosome parasite is a vulnerable element to the survival of the worm and has steered attempts toward the use of redox-directed bioorganometallic compounds. Disruption of the schistosome redox homeostasis through organometallic ions provides a novel drug target that could be used in overcoming the drawbacks of the mainstream drug and one that could possibly bypass the emergence of drug resistance.

show abstract

“…The worm burden reductions were 12%, 88% and 75%, respectively. The additional fact that the Fe 2+ complex exhibited an activity comparable to that of praziquantel must be deemed a strong indication of a novel drug lead for schistosomiasis [74]. …”

Section: Research and Development Of Antischistosomal Drugsmentioning

confidence: 99%

Controlling schistosomiasis with praziquantel: How much longer without a viable alternative?

Bergquist¹,

2017

Self Cite

View full text Add to dashboard Cite

The current approach of morbidity control of schistosomiasis, a helminth disease of poverty with considerable public health and socioeconomic impact, is based on preventive chemotherapy with praziquantel. There is a pressing need for new drugs against this disease whose control entirely depends on this single drug that has been widely used over the past 40 years. We argue that a broader anthelminthic approach supplementing praziquantel with new antischistosomals targeting different parasite development stages would not only increase efficacy but also reduce the risk for drug resistance. Repositioning drugs already approved for other diseases provides a shortcut to clinical trials, as it is expected that such drugs rapidly pass the regulatory authorities. The antischistosomal properties of antimalarial drugs (e.g., semisynthetic artemisinins, synthetic trioxolanes, trioxaquines and mefloquine) and of drugs being developed or registered for other purposes (e.g., moxidectin and miltefosin), administered alone or in combination with praziquantel, have been tested in the laboratory and clinical trials. Another avenue to follow is the continued search for new antischistosomal properties in plants. Here, we summarise recent progress made in schistosomiasis chemotherapy, placing particular emphasis on repositioning of existing drugs against schistosomiasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s40249-017-0286-2) contains supplementary material, which is available to authorized users.

show abstract

Discovery of Antischistosomal Drug Leads Based on Tetraazamacrocyclic Derivatives and Their Metal Complexes

Cited by 27 publications

References 37 publications

Investigations into the Structure/Antibacterial Activity Relationships of Cyclam and Cyclen Derivatives

Investigations into the Structure/Antibacterial Activity Relationships of Cyclam and Cyclen Derivatives

Bioorganometallic Compounds as Novel Drug Targets against Schistosomiasis in Sub-Saharan Africa: An alternative to Praziquantel?

Controlling schistosomiasis with praziquantel: How much longer without a viable alternative?

Contact Info

Product

Resources

About