22 results on '"Conor R. Caffrey"'
Search Results
2. Structure activity relationships of antischistosomal N-phenylbenzamides by incorporation of electron-withdrawing functionalities
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Ameera Mohammed Dawoodjee, John Sichinga, Harrison Banda, Steve Mbaya, Evelyn Funjika, Godfrey Mayoka, Christabel Hikaambo, Karol R. Francisco, Yujie Uli Sun, Lawrence J. Liu, Conor R. Caffrey, and Peter Mubanga Cheuka
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N-phenylbenzamide analogs ,N-pyridazinylbenzamide analogs ,Schistosoma mansoni ,Chemistry ,QD1-999 - Abstract
For the adult Schistosoma mansoni flatworm pathogen, we report further structure activity relationships (SAR) of 19 N-phenylbenzamide analogs. Our previous SAR studies, designed by selecting representative substituents from the Craig plot, identified 9 and 11 which possessed electron-withdrawing groups that benefited potency. This study sought to enhance the potency of this chemotype by incorporating other electron-withdrawing functionalities not studied previously and to overcome the potential pharmacokinetic liabilities associated with the high lipophilicity of frontrunner compounds. Compared to the most potent compound, 9 (EC50 = 80 nM), from our previous work, the most potent compounds in the current study (32 (EC50 = 1.17 µM), 34 (EC50 = 1.64 µM) and 38 (EC50 = 1.16 µM)) were less active although they retained single digit micromolar potency. Furthermore, compound 38 generated a CC50 value of > 20 µM in counter toxicity screens using HEK 293 cells, translating to a wide selectivity index of > 17.
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- 2024
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3. Pharmacophore Virtual Screening Identifies Riboflavin as an Inhibitor of the Schistosome Cathepsin B1 Protease with Antiparasitic Activity
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Ramon M. Cogo, Thaís F. A. Pavani, Ana C. A. Mengarda, Rayssa A. Cajas, Thainá R. Teixeira, Lucas Fukui-Silva, Yujie Uli Sun, Lawrence J. Liu, Dilini K. Amarasinghe, Michael C. Yoon, Osvaldo A. Santos-Filho, Josué de Moraes, Conor R. Caffrey, and Daniela G. G. Rando
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Chemistry ,QD1-999 - Published
- 2024
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4. Computational Workflow to Design Novel Vaccine Candidates and Small-Molecule Therapeutics for Schistosomiasis
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Emmanuel Oluwadare Balogun, Gideon Ibrahim Joseph, Samuel Charles Olabode, Naziru Abdulkadir Dayaso, Ammar Usman Danazumi, Rachael Bashford-Rogers, James H. Mckerrow, Ghulam Jeelani, and Conor R. Caffrey
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Schistosoma ,drug and vaccine ,immunoinformatics ,cathepsin proteases ,Medicine - Abstract
Human schistosomiasis, caused by the Schistosoma trematode, is a neglected parasitic disease affecting over 250 million people worldwide. There is no vaccine, and the single available drug is threatened by drug resistance. This study presents a computational approach to designing multiepitope vaccines (MEVs) targeting the cercarial (CMEV) and schistosomular (SMEV) stages of schistosomes, and identifies potential schistosomicidal compounds from the Medicine for Malaria Ventures (MMV) and SuperNatural Database (SND) libraries. The designed vaccines (CMEV and SMEV) are engineered to provoke robust immune responses by incorporating a blend of T- and B-cell epitopes. Structural and immunoinformatics evaluations predicted robust interactions of CMEV and SMEV with key immune receptors and prolonged immune responses. In addition, molecular docking identified several compounds from the MMV and SND libraries with strong binding affinities to vital Schistosoma cathepsin proteases, indicating their potential as schistosomicidal agents. Our findings contribute to the potential development of effective vaccines and drugs against schistosomiasis.
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- 2024
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5. Seaweeds and Corals from the Brazilian Coast: Review on Biotechnological Potential and Environmental Aspects
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Gustavo Souza dos Santos, Thais Luz de Souza, Thaiz Rodrigues Teixeira, João Pedro Cezário Brandão, Keila Almeida Santana, Luan Henrique Santos Barreto, Samantha de Souza Cunha, Daniele Cristina Muniz Batista dos Santos, Conor R. Caffrey, Natan Silva Pereira, and Aníbal de Freitas Santos Júnior
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Brazilian shoreline ,seaweeds ,corals ,secondary metabolites ,bioactivity ,nutrients ,Organic chemistry ,QD241-441 - Abstract
Brazil has a megadiversity that includes marine species that are distributed along 800 km of shoreline. This biodiversity status holds promising biotechnological potential. Marine organisms are important sources of novel chemical species, with applications in the pharmaceutical, cosmetic, chemical, and nutraceutical fields. However, ecological pressures derived from anthropogenic actions, including the bioaccumulation of potentially toxic elements and microplastics, impact promising species. This review describes the current status of the biotechnological and environmental aspects of seaweeds and corals from the Brazilian coast, including publications from the last 5 years (from January 2018 to December 2022). The search was conducted in the main public databases (PubChem, PubMed, Science Direct, and Google Scholar) and in the Espacenet database (European Patent Office—EPO) and the Brazilian National Property Institute (INPI). Bioprospecting studies were reported for seventy-one seaweed species and fifteen corals, but few targeted the isolation of compounds. The antioxidant potential was the most investigated biological activity. Despite being potential sources of macro- and microelements, there is a literature gap regarding the presence of potentially toxic elements and other emergent contaminants, such as microplastics, in seaweeds and corals from the Brazilian coast.
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- 2023
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6. Biomechanical interactions of Schistosoma mansoni eggs with vascular endothelial cells facilitate egg extravasation
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Yi-Ting Yeh, Danielle E. Skinner, Ernesto Criado-Hidalgo, Natalie Shee Chen, Antoni Garcia-De Herreros, Nelly El-Sakkary, Lawrence Liu, Shun Zhang, Adithan Kandasamy, Shu Chien, Juan C. Lasheras, Juan C. del Álamo, and Conor R. Caffrey
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Immunologic diseases. Allergy ,RC581-607 ,Biology (General) ,QH301-705.5 - Abstract
The eggs of the parasitic blood fluke, Schistosoma, are the main drivers of the chronic pathologies associated with schistosomiasis, a disease of poverty afflicting approximately 220 million people worldwide. Eggs laid by Schistosoma mansoni in the bloodstream of the host are encapsulated by vascular endothelial cells (VECs), the first step in the migration of the egg from the blood stream into the lumen of the gut and eventual exit from the body. The biomechanics associated with encapsulation and extravasation of the egg are poorly understood. We demonstrate that S. mansoni eggs induce VECs to form two types of membrane extensions during encapsulation; filopodia that probe eggshell surfaces and intercellular nanotubes that presumably facilitate VEC communication. Encapsulation efficiency, the number of filopodia and intercellular nanotubes, and the length of these structures depend on the egg’s vitality and, to a lesser degree, its maturation state. During encapsulation, live eggs induce VEC contractility and membranous structures formation in a Rho/ROCK pathway-dependent manner. Using elastic hydrogels embedded with fluorescent microbeads as substrates to culture VECs, live eggs induce VECs to exert significantly greater contractile forces during encapsulation than dead eggs, which leads to 3D deformations on both the VEC monolayer and the flexible substrate underneath. These significant mechanical deformations cause the VEC monolayer tension to fluctuate with the eventual rupture of VEC junctions, thus facilitating egg transit out of the blood vessel. Overall, our data on the mechanical interplay between host VECs and the schistosome egg improve our understanding of how this parasite manipulates its immediate environment to maintain disease transmission. Author summary Schistosomiasis, which infects over 200 million people, is a painful disease of poverty that is caused by inflammatory responses to the Schistosoma blood fluke’s eggs. To continue the parasite’s life cycle, eggs must escape the blood vessels and migrate through tissues of the host to the alimentary canal for exit into the environment. The biomechanical processes that help the immobile eggs to cross the blood vessel’s vascular endothelial cells (VECs) as the first step in this migration are not understood. We found that live but not dead eggs induce VECs to crawl over and encapsulate them. VECs in contact with live eggs make membranous extensions (filopodia) to explore the egg’s surface and also form long intercellular nanotubes to communicate with neighboring cells. VECs stimulate particular (Rho/ROCK) biochemical pathways to increase cell contractility and the forces generated are large enough to eventually break the junctions between cells and allow passage of the eggs into the underlying tissue. Our findings show how schistosome eggs activate and interact with VECs to initiate their escape from the bloodstream.
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- 2022
7. A Broad Spectrum Antiparasitic Activity of Organotin (IV) Derivatives and Its Untargeted Proteomic Profiling Using Leishmania donovani
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Obaid Hayat, Nazif Ullah, Muhammad Sirajuddin, Miriam A. Giardini, Jennifer V. Nguyen, Karol R. Francisco, Lawrence J. Liu, Yujie Uli Sun, Svetlana Maurya, Dominic McGrosso, David J. Gonzalez, Conor R. Caffrey, Anjan Debnath, and Jair L. Siqueira-Neto
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organotin (IV) compounds ,antiparasitic activity ,neglected tropical diseases ,drug discovery ,Medicine - Abstract
Metals have been used in medicine since ancient times for the treatment of different ailments with various elements such as iron, gold and arsenic. Metal complexes have also been reported to show antibiotic and antiparasitic activity. In this context, we tested the antiparasitic potential of 10 organotin (IV) derivatives from 4-(4-methoxyphenylamino)-4 oxobutanoic acid (MS26) against seven eukaryotic pathogens of medical importance: Leishmania donovani, Trypanosoma cruzi, Trypanosoma brucei, Entamoeba histolytica, Giardia lamblia, Naegleria fowleri and Schistosoma mansoni. Among the compounds with and without antiparasitic activity, compound MS26Et3 stood out with a 50% effective concentration (EC50) of 0.21 and 0.19 µM against promastigotes and intracellular amastigotes of L. donovani, respectively, 0.24 µM against intracellular amastigotes of T. cruzi, 0.09 µM against T. brucei, 1.4 µM against N. fowleri and impaired adult S. mansoni viability at 1.25 µM. In terms of host/pathogen selectivity, MS26Et3 demonstrated relatively mild cytotoxicity toward host cells with a 50% viability concentration of 4.87 µM against B10R cells (mouse monocyte cell line), 2.79 µM against C2C12 cells (mouse myoblast cell line) and 1.24 µM against HEK923 cells (human embryonic kidney cell line). The selectivity index supports this molecule as a therapeutic starting point for a broad spectrum antiparasitic alternative. Proteomic analysis of host cells infected with L. donovani after exposure to MS26Et3 showed a reduced expression of Rab7, which may affect the fusion of the endosome with the lysosome, and, consequently, impairing the differentiation of L. donovani to the amastigote form. Future studies to investigate the molecular target(s) and mechanism of action of MS26Et3 will support its chemical optimization.
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- 2022
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8. Perspective on Schistosomiasis Drug Discovery: Highlights from a Schistosomiasis Drug Discovery Workshop at Wellcome Collection, London, September 2022
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Nicola Caldwell, Rana Afshar, Beatriz Baragaña, Amaya L. Bustinduy, Conor R. Caffrey, James J. Collins, Daniela Fusco, Amadou Garba, Mark Gardner, Mireille Gomes, Karl F. Hoffmann, Michael Hsieh, Nathan C. Lo, Case W. McNamara, Justin Komguep Nono, Gilda Padalino, Kevin D. Read, Meta Roestenberg, Thomas Spangenberg, Sabine Specht, and Ian H. Gilbert
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Infectious Diseases - Published
- 2023
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9. Identification of Inhibitors of the Schistosoma mansoni VKR2 Kinase Domain
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Indran Mathavan, Lawrence J. Liu, Sean W. Robinson, Nelly El-Sakkary, Adam Jo J. Elatico, Darwin Gomez, Ricky Nellas, Raymond J. Owens, William Zuercher, Iva Navratilova, Conor R. Caffrey, Konstantinos Beis, and Medical Research Council
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crystal structure ,Science & Technology ,0304 Medicinal and Biomolecular Chemistry ,Organic Chemistry ,HIV ,Chemistry, Medicinal ,0305 Organic Chemistry ,Biochemistry ,inhibitor ,inhibition of autophosphorylation ,schistosomiasis ,docking ,Drug Discovery ,Schistosoma ,Pharmacology & Pharmacy ,GENITAL SCHISTOSOMIASIS ,PRAZIQUANTEL ,1115 Pharmacology and Pharmaceutical Sciences ,Life Sciences & Biomedicine ,kinase domain - Abstract
Schistosomiasis is a neglected tropical disease caused by parasitic flatworms. Current treatment relies on just one partially effective drug, praziquantel (PZQ). Schistosoma mansoni Venus Kinase Receptors 1 and 2 (SmVKR1 and SmVKR2) are important for parasite growth and egg production, and are potential targets for combating schistosomiasis. VKRs consist of an extracellular Venus Flytrap Module (VFTM) linked via a transmembrane helix to a kinase domain. Here, we initiated a drug discovery effort to inhibit the activity of the SmVKR2 kinase domain (SmVKR2KD) by screening the GSK published kinase inhibitor set 2 (PKIS2). We identified several inhibitors, of which four were able to inhibit its enzymatic activity and induced phenotypic changes in ex vivoS. mansoni. Our crystal structure of the SmVKR2KD displays an active-like state that sheds light on the activation process of VKRs. Our data provide a basis for the further exploration of SmVKR2 as a possible drug target.
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- 2022
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10. Brain Microvascular Transcriptional Responses to African Trypanosomes Under Physiologic Flow
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Pathology (PAT), SOM, Dennis Grab, Nur Atiqah Azhar, Mohammad Asif Khan, Brandon J. Sumpio, Yongqing Zhang, Kevin G. Becker, Carlos Pardo-Villamizar, Koichiro Mihara, Morley Hollenberg, Conor R. Caffrey, H. Benjamin Larman, Andrew Wong, Peter Searson, Peter G. E. Kennedy, Serap Aksoy, Bauer E.Sumpio, Pathology (PAT), SOM, Dennis Grab, and Nur Atiqah Azhar, Mohammad Asif Khan, Brandon J. Sumpio, Yongqing Zhang, Kevin G. Becker, Carlos Pardo-Villamizar, Koichiro Mihara, Morley Hollenberg, Conor R. Caffrey, H. Benjamin Larman, Andrew Wong, Peter Searson, Peter G. E. Kennedy, Serap Aksoy, Bauer E.Sumpio
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Breakout Session: Mental Health and Traumatic Brain Injury Human Brain Microvascular Transcriptional Responses to African Trypanosomes Under Physiologic Flow. Dennis J Grab1, Nur Atiqah Azhar2, Mohammad Asif Khan2, Brandon J. Sumpio3, Yongqing Zhang4, Kevin G Becker4, Carlos Pardo-Villamizar5, Koichiro Mihara6, Morley Hollenberg6, Conor R. Caffrey7, H. Benjamin Larman5, Andrew Wong5, Peter Searson5, Peter G E Kennedy8, Serap Aksoy3, Bauer E.Sumpio3. 1] 1Uniformed Services University of the Health Sciences, Bethesda, MD, USA. 2Perdana University, Selangor, Malaysia. 3Yale University, New Haven, CT, USA. 4National Institute on Aging (NIH), Baltimore, Maryland USA. 5Johns Hopkins University, Baltimore, MD, USA. 6University of Calgary Cumming School of Medicine, Calgary, Canada. 7University of California San Diego, La Jolla, USA. 8University of Glasgow, Glasgow, Scotland, UK. Disclaimer: The opinions expressed herein are those of the author(s) and are not necessarily representative of those of the Uniformed Services University of the Health Sciences, the Department of Defense, or the United States Army, Navy, or Air Force. MHSRS-23-10694 INTRODUCTION: The African trypanosome, Trypanosoma brucei rhodesiense (Tbr), causes the acute East African variant of human African trypanosomiasis (HAT; sleeping sickness). Dissemination into the brain leads to neurologic involvement characterized by concomitant psychiatric disorders, seizures, night- time insomnia, and daytime drowsiness, progressive coma and, if untreated, death. How African trypanosomes alter the human blood-brain barrier (BBB) function to enter and/or disrupt brain homeostasis and cause central nervous system disease is of vital importance but not fully understood. Gold standard” static in vitro model systems (Transwell™ inserts and Electric Cell-Substrate Electric Impedance Sensing; ECIS) for BBB studies using shuman brain microvascular endothelial cells (MEC) show strong links between BBB dysfunction, pathogen cy, RITM0041103, INTRODUCTION: The African trypanosome, Trypanosoma brucei rhodesiense (Tbr), causes the acute East African variant of human African trypanosomiasis (HAT; sleeping sickness). Dissemination into the brain leads to neurologic involvement characterized by concomitant psychiatric disorders, seizures, night- time insomnia, and daytime drowsiness, progressive coma and, if untreated, death. How African trypanosomes alter the human blood-brain barrier (BBB) function to enter and/or disrupt brain homeostasis and cause central nervous system disease is of vital importance but not fully understood. Gold standard” static in vitro model systems (Transwell™ inserts and Electric Cell-Substrate Electric Impedance Sensing; ECIS) for BBB studies using shuman brain microvascular endothelial cells (MEC) show strong links between BBB dysfunction, pathogen cysteine proteases as major virulence factors (iTbCatL), host protease-activated receptors (PARs) and Ca2+ signaling (Fig 1; Refs 1-3). Infection-induced BMEC proinflammatory cytokine expression and gene-profiling identified pathways that predict G-protein modulation of BBB permeability. In human kidney embryonic cells, recombinant trypanosome cysteine protease TbCatL triggers biased MAPK signaling via PAR1, but not PAR2 and MAPK signaling by both PARs is triggered by other proteases present in trypanosome lysate preparations (Fig 2: unpbublished). The consequence of these events was predicted to be increased permeability of the BBB to parasite transmigration and the initiation of neuroinflammation, events precursory to CNS disease. These static BBB models provided important and predictive information about the early stages of CNS HAT predicting that the parasites would enter the brain of a mouse within hours after entering the bloodstream (Fig 3; Ref 4). However, these models do not address the contribution of brain blood flow dynamics (Ref 5).
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- 2023
11. Development of subunit selective substrates for Trichomonas vaginalis proteasome
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Pavla Fajtova, Brianna M Hurysz, Yukiko Miyamoto, Mateus Serafim, Zhenze Jiang, Diego F. Trujillo, Lawrence Liu, Urvashi Somani, Jehad Almaliti, Samuel A. Myers, Conor R. Caffrey, William H. Gerwick, Christopher J Kirk, Evzen Boura, Lars Eckmann, and Anthony J O’Donoghue
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Article - Abstract
The protozoan parasite,Trichomonas vaginalis(Tv) causes trichomoniasis, the most common, non-viral, sexually transmitted infection in the world. Only two closely related drugs are approved for its treatment. The accelerating emergence of resistance to these drugs and lack of alternative treatment options poses an increasing threat to public health. There is an urgent need for novel effective anti-parasitic compounds. The proteasome is a critical enzyme forT. vaginalissurvival and was validated as a drug target to treat trichomoniasis. However, to develop potent inhibitors of theT. vaginalisproteasome, it is essential that we understand which subunits should be targeted. Previously, we identified two fluorogenic substrates that were cleaved byT. vaginalisproteasome, however after isolating the enzyme complex and performing an in-depth substrate specificity study, we have now designed three fluorogenic reporter substrates that are each specific for one catalytic subunit. We screened a library of peptide epoxyketone inhibitors against the live parasite and evaluated which subunits are targeted by the top hits. Together we show that targeting of the β5 subunit ofT. vaginalisis sufficient to kill the parasite, however, targeting of β5 plus either β1 or β2 results in improved potency.
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- 2023
12. Brazilian green propolis reduces worm burden and hepatic granuloma formation in a Schistosoma mansoni experimental murine model
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Lucas A. de L. Paula, Mário F. C. Santos, Mariana C. Pagotti, Rodrigo C. S. Veneziani, Jairo K. Bastos, Conor R. Caffrey, Sérgio R. Ambrósio, and Lizandra G. Magalhães
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Infectious Diseases ,General Veterinary ,Insect Science ,Parasitology ,General Medicine - Published
- 2022
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13. Structure-Activity Relationships, Tolerability and Efficacy of Microtubule-Active 1,2,4-Triazolo[1,5-a]pyrimidines as Potential Candidates to Treat Human African Trypanosomiasis
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Ludovica Monti, Lawrence J. Liu, Carmine Varricchio, Bobby Lucero, Thibault Alle, Wenqian Yang, Ido Bem-Shalom, Michael Gilson, Kurt R. Brunden, Andrea Brancale, Conor R. Caffrey, and Carlo Ballatore
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Article - Abstract
Tubulin and microtubules (MTs) are potential protein targets to treat parasitic infections and our previous studies have shown that the triazolopyrimidine (TPD) class of MT- active compounds hold promise as antitrypanosomal agents. MT-targeting TPDs include structurally related but functionally diverse congeners that interact with mammalian tubulin at either one or two distinct interfacial binding sites; namely, the seventh and vinca sites, which are found within or between α,β-tubulin heterodimers, respectively. Evaluation of the activity of 123 TPD congeners against culturedTrypanosoma bruceienabled a robust quantitative structure-activity relationship (QSAR) model and the prioritization of two congeners forin vivopharmacokinetics (PK), tolerability and efficacy studies. Treatment ofT. brucei-infected mice with tolerable doses of TPDs3and4significantly decreased blood parasitemia within 24 h. Further, two once-weekly doses of4at 10 mg/kg significantly extended the survival of infected mice relative to infected animals treated with vehicle. Further optimization of dosing and/or the dosing schedule of these CNS-active TPDs may provide alternative treatments for human African trypanosomiasis.
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- 2023
14. Activity of N-phenylbenzamide analogs against the neglected disease pathogen, Schistosoma mansoni
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Masebe Kanyanta, Chilufya Lengwe, Dickson Mambwe, Karol R. Francisco, Lawrence J. Liu, Yujie Uli Sun, Dilini K. Amarasinghe, Conor R. Caffrey, and Peter Mubanga Cheuka
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Organic Chemistry ,Clinical Biochemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Molecular Biology ,Biochemistry ,Article - Abstract
For the Schistosoma mansoni flatworm pathogen, we report a structure–activity relationship of 25 derivatives of the N-phenylbenzamide compound, 1 (MMV687807), a Medicines for Malaria Venture compound for which bioactivity was originally identified in 2018. Synthesized compounds were cross-screened against the HEK 293 mammalian cells. Compounds 9 and 11 were identified as fast-acting schistosomicidal compounds whereby adult worm integrity was severely compromised within 1 h. Against HEK 293 mammalian cells, both compounds exhibited high CC(50) values (9.8 ± 1.6 and 11.1 ± 0.2 μM respectively) which could translate to comfortable selectivity. When evaluated in a concentration-response format, compound 9 was active in the nanomolar range (EC(50) = 80 nM), translating to a selectivity index of 123 over HEK 293 cells. The data encourage the further investigation of N-phenylbenzamides as antischistosomals.
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- 2023
15. Structure-Activity Relationship of Dibenzylideneacetone Analogs Against the Neglected Disease Pathogen, Trypanosoma brucei
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Karol R. Francisco, Ludovica Monti, Wenqian Yang, Hayoung Park, Lawrence J. Liu, Kaitlyn Watkins, Dilini K. Amarasinghe, Marianna Nalli, Carlos Roberto Polaquini, Luis O. Regasini, Antônio Eduardo Miller Crotti, Romano Silvestri, Lizandra Guidi Magalhães, and Conor R. Caffrey
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Organic Chemistry ,Clinical Biochemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Molecular Biology ,Biochemistry ,Article - Abstract
Trypanosoma brucei is a protozoan parasite that causes Human African Trypanosomiasis (HAT), a neglected tropical disease (NTD) that is endemic in 36 countries in sub-Saharan Africa. Only a handful drugs are available for treatment, and these have limitations, including toxicity and drug resistance. Using the natural product, curcumin, as a starting point, several curcuminoids and related analogs were evaluated against bloodstream forms of T. b. brucei. A particular subset of dibenzylideneacetone (DBA) compounds exhibited potent in vitro antitrypanosomal activity with sub-micromolar EC(50) values. A structure-activity relationship study including 26 DBA analogs was initiated, and several compounds exhibited EC(50) values as low as 200 nM. Cytotoxicity counter screens in HEK293 cells identified several compounds having selectivity indices above 10. These data suggest that DBAs offer starting points for a new small molecule therapy of HAT.
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- 2023
16. Microtubule-Stabilizing 1,2,4-Triazolo[1,5-a]pyrimidines as Candidate Therapeutics for Neurodegenerative Disease: Matched Molecular Pair Analyses and Computational Studies Reveal New Structure-Activity Insights
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Thibault Alle, Carmine Varricchio, Yuemang Yao, Bobby Lucero, Goodwell Nzou, Stefania Demuro, Megan Muench, Khoa D. Vuong, Killian Oukoloff, Anne-Sophie Cornec, Karol R. Francisco, Conor R. Caffrey, Virginia M.-Y. Lee, Amos B. Smith, Andrea Brancale, Kurt R. Brunden, and Carlo Ballatore
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Aging ,Medicinal & Biomolecular Chemistry ,Organic Chemistry ,Neurosciences ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Neurodegenerative Diseases ,Pharmacology and Pharmaceutical Sciences ,Neurodegenerative ,Alzheimer's Disease ,Microtubules ,Brain Disorders ,Structure-Activity Relationship ,Medicinal and Biomolecular Chemistry ,Pyrimidines ,Alzheimer Disease ,Tubulin ,Drug Discovery ,Neurological ,Acquired Cognitive Impairment ,Molecular Medicine ,Humans ,Dementia - Abstract
Microtubule (MT)-stabilizing 1,2,4-triazolo[1,5-a]pyrimidines (TPDs) hold promise as candidate therapeutics for Alzheimer's disease (AD) and other neurodegenerative conditions. However, depending on the choice of substituents around the TPD core, these compounds can elicit markedly different cellular phenotypes that likely arise from the interaction of TPD congeners with either one or two spatially distinct binding sites within tubulin heterodimers (i.e., the seventh site and the vinca site). In the present study, we report the design, synthesis, and evaluation of a series of new TPD congeners, as well as matched molecular pair analyses and computational studies, that further elucidate the structure-activity relationships of MT-active TPDs. These studies led to the identification of novel MT-normalizing TPD candidates that exhibit favorable ADME-PK, including brain penetration and oral bioavailability, as well as brain pharmacodynamic activity.
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- 2023
17. Coumarin-based derivatives targeting Trypanosoma cruzi cruzain and Trypanosoma brucei cathepsin L-like proteases
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Jéssica Alves Nunes, Fabrícia Nunes da Silva, Elany Barbosa da Silva, Clara Andrezza Crisóstomo Bezerra Costa, Johnnatan Duarte de Freitas, Francisco Jaime Bezerra Mendonça-Junior, Miriam Aparecida Giardini, Jair Lage de Siqueira-Neto, James H. McKerrow, Thaiz Rodrigues Teixeira, Louis William Odeesho, Conor R. Caffrey, Sílvia Helena Cardoso, and Edeildo Ferreira da Silva-Júnior
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Materials Chemistry ,General Chemistry ,Catalysis - Abstract
Trypanosoma cruzi (Chagas diseases – also named American trypanosomiasis) and T. brucei (human African trypanosomiasis – HAT) negatively impact public health, being endemic in several countries and leading to thousands of deaths per year.
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- 2023
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18. Microtubule-Stabilizing 1,2,4-Triazolo[1,5
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Thibault, Alle, Carmine, Varricchio, Yuemang, Yao, Bobby, Lucero, Goodwell, Nzou, Stefania, Demuro, Megan, Muench, Khoa D, Vuong, Killian, Oukoloff, Anne-Sophie, Cornec, Karol R, Francisco, Conor R, Caffrey, Virginia M-Y, Lee, Amos B, Smith, Andrea, Brancale, Kurt R, Brunden, and Carlo, Ballatore
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Microtubule (MT)-stabilizing 1,2,4-triazolo[1,5
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- 2022
19. Discovery of pH-Selective Marine and Plant Natural Product Inhibitors of Cathepsin B Revealed by Screening at Acidic and Neutral pH Conditions
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Von V. Phan, Charles Mosier, Michael C. Yoon, Evgenia Glukhov, Conor R. Caffrey, Anthony J. O’Donoghue, William H. Gerwick, and Vivian Hook
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General Chemical Engineering ,General Chemistry ,Materials Engineering ,Chemical Engineering - Abstract
Dysregulation of cathepsin B, which involves the translocation of the enzyme from acidic pH lysosomes to the neutral pH cytosol, followed by the initiation of cell death and inflammation, occurs in numerous brain disorders. The wide difference in the acidic pH (4.6) of lysosomes compared to the neutral pH (7.2) of the cytosol suggests that screening at different pH conditions may identify pH-selective modulators of cathepsin B. Therefore, a collection of pure marine and plant natural product (NP) compounds, with synthetic compounds, was screened at pH 4.6 and pH 7.2 in cathepsin B assays, which led to the identification of GER-12 (Crossbyanol B) and GER-24 ((7Z,9Z,12Z)-octadeca-7,9,12-trien-5-ynoic acid) marine NP inhibitors at acidic pH but not at neutral pH. GER-12 was effective for the reversible inhibition of cathepsin B, with an IC50 of 3 μM. GER-24 had an IC50 of 16 μM and was found to be an irreversible inhibitor. These results show that NP screening at distinct biological pH conditions can lead to the identification of pH-selective cathepsin B modulators. These findings suggest that screening efforts for molecular probes and drug discovery may consider the biological pH environment of the target in the disease process.
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- 2022
20. EF24, a schistosomicidal curcumin analog: Insights from its synthesis and phenotypic, biochemical and cytotoxic activities
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Fernanda R. Badoco, Lucas A.L. Paula, Renato P. Orenha, Tiago M.F. Mendes, Iara S. Squarisi, Nelly El-Sakkary, Messias C. Loiola, Naftale Katz, Denise C. Tavares, Mirela I. Sairre, Renato Luis T. Parreira, Fernanda Janku Cabral, Silmara M. Alegretti, Conor R. Caffrey, and Lizandra G. Magalhães
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Male ,Mammals ,Glutathione Peroxidase ,Curcumin ,Schistosoma mansoni ,General Medicine ,Toxicology ,Antioxidants ,Praziquantel ,Schistosomicides ,Glutathione Reductase ,Animals ,Schistosomiasis ,Female ,Reactive Oxygen Species ,Glutathione Transferase - Abstract
Praziquantel (PZQ) is the only drug available for community-based control programs which aim to reduce the prevalence and morbidity associated with schistosomiasis. Here, we synthesized and evaluated the schistosomicidal, biochemical and cytotoxic activities of EF24, a synthetic curcumin analog, against different isolates of Schistosoma mansoni. EF24 elicited marked phenotypic alterations at 10 μM against schistosomula and 42-day-old adult worms of the Naval Medical Research Institute (NMRI) isolate. EF24 had 50% effective concentration (EC
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- 2022
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21. From rational design to serendipity: Discovery of novel thiosemicarbazones as potent trypanocidal compounds
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Saulo Fehelberg Pinto Braga, Viviane Corrêa Santos, Rafael Pinto Vieira, Elany Barbosa da Silva, Ludovica Monti, Susann H. Krake, Pablo D.G. Martinez, Luiz Carlos Dias, Conor R. Caffrey, Jair L. Siqueira-Neto, Renata Barbosa de Oliveira, and Rafaela Salgado Ferreira
- Subjects
Thiosemicarbazones ,Pharmacology ,Structure-Activity Relationship ,Trypanosoma cruzi ,Trypanosoma brucei brucei ,Organic Chemistry ,Drug Discovery ,Humans ,Chagas Disease ,General Medicine ,Cysteine Proteinase Inhibitors ,Trypanocidal Agents - Abstract
Chagas disease is a major public health problem caused by Trypanosoma cruzi, with an estimated 6-7 million people infected and 70 million at risk of infection. T. brucei gambiense and T. brucei rhodesiense are two subspecies of related parasites that cause human African trypanosomiasis, a neglected tropical disease with also millions of people at risk of infection. Pharmacotherapy for both diseases suffers from low efficacy, side effects, or drug resistance. Recently, we reported a noncovalent competitive inhibitor of cruzain (IC
- Published
- 2022
- Full Text
- View/download PDF
22. Designing and development of phthalimides as potent anti-tubulin hybrid molecules against malaria
- Author
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Vigyasa Singh, Rahul Singh Hada, Ravi Jain, Manu Vashistha, Geeta Kumari, Snigdha Singh, Neha Sharma, Meenakshi Bansal, null Poonam, Martin Zoltner, Conor R. Caffrey, Brijesh Rathi, and Shailja Singh
- Subjects
Pharmacology ,Antimalarials ,Mice ,Plasmodium berghei ,Tubulin ,Plasmodium falciparum ,Organic Chemistry ,Drug Discovery ,Animals ,Phthalimides ,General Medicine ,Malaria - Abstract
Constant emergence of drug-resistant Plasmodium falciparum warrants urgent need for effective and inexpensive drugs. Herein, phthalimide (Pht) analogs possessing the bioactive scaffolds, benzimidazole and 1,2,3-triazole, were evaluated for in vitro and in vivo anti-plasmodial activity without any apparent hemolysis, or cytotoxicity. Analogs 4(a-e) inhibited the growth of 3D7 and RKL-9 strains at submicromolar concentrations. Defects were observed during parasite egress from or invasion of the red blood cells. Mitochondrial membrane depolarization was measured as one of the causes of cell death. Phts 4(a-e) in combination with artemisinin exhibited two-to three-fold increased efficacy. Biophysical and biochemical analysis suggest that Pht analogs mediate plasmodial growth inhibition by interacting with tubulin protein of the parasite. Lastly, Phts 4(a-e) significantly decreased parasitemia and extended host survival in murine model Plasmodium berghei ANKA infection. Combined, the data indicate that Pht analogs should be further explored, which could offer novel value to the antimalarial drug development pipeline.
- Published
- 2022
- Full Text
- View/download PDF
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