Archives: Publication

Published in: European Journal of Medicinal Chemistry, Volume 276, 5 October 2024, 116677

DOI: 10.1016/j.ejmech.2024.116677

Authors: Petar P.S. Calic, Trent D. Ashton, Mahta Mansouri, Katie Loi, KateE. Jarman, Deyun Qiu, Adele M. Lehane, Sayantan Roy [TCGLS Member], Gunturu P. Rao [TCGLS Member], Bikash Maity [TCGLS Member], Sergio Wittlin, Benigno Crespo, Franciso-Javier Gamo, Ioanna Deni, David A. Fidock, Mrittika Chowdury, Tania F. de Koning-Ward, Alan F. Cowman, Paul F. Jackson, Delphine Baud,  Stephen Brand, Benoît Laleu, Brad E. Sleebs

Abstract: Emerging resistance to current antimalarials is reducing their effectiveness and therefore there is a need to develop new antimalarial therapies. Toward this goal, high throughput screens against the P. falciparum asexual parasite identified the pyrazolopyridine 4-carboxamide scaffold. Structure-activity relationship analysis of this chemotype defined that the N1-tert-butyl group and aliphatic foliage in the 3- and 6-positions were necessary for activity, while the inclusion of a 7′-aza-benzomorpholine on the 4-carboxamide motif resulted in potent anti-parasitic activity and increased aqueous solubility. A previous report that resistance to the pyrazolopyridine class is associated with the ABCI3 transporter was confirmed, with pyrazolopyridine 4-carboxamides showing an increase in potency against parasites when the ABCI3 transporter was knocked down. The low metabolic stability intrinsic to the pyrazolopyridine scaffold and the slow rate by which the compounds kill asexual parasites resulted in poor performance in a P. berghei asexual blood stage mouse model. Lowering the risk of resistance and mitigating the metabolic stability and cytochrome P450 inhibition will be challenges in the future development of the pyrazolopyrimidine antimalarial class.

Graphical Abstract

Published in: Journal of Medicinal Chemistry, ASAP

DOI: 10.1021/acs.jmedchem.4c01241

Authors: Trent D. Ashton, Petar P. S. Calic, Madeline G. Dans, Zi Kang Ooi, Qingmiao Zhou, Josephine Palandri, Katie Loi, Kate E. Jarman, Deyun Qiu, Adele M. Lehane, Bikash Chandra Maity[TCGLS Member], Nirupam De[TCGLS Member],Carlo Giannangelo, Christopher A. MacRaild, Darren J. Creek, Emma Y. Mao, Maria R. Gancheva, Danny W. Wilson, Mrittika Chowdury, Tania F. de Koning-Ward, Mufuliat T. Famodimu,Michael J. Delves, Harry Pollard, Colin J. Sutherland, Delphine Baud, Stephen Brand, Paul F. Jackson, Alan F. Cowman, and Brad E. Sleebs

Abstract: To contribute to the global effort to develop new antimalarial therapies, we previously disclosed initial findings on the optimization of the dihydroquinazolinone-3-carboxamide class that targets PfATP4. Here we report on refining the aqueous solubility and metabolic stability to improve the pharmacokinetic profile and consequently in vivo efficacy. We show that the incorporation of heterocycle systems in the 8-position of the scaffold was found to provide the greatest attainable balance between parasite activity, aqueous solubility, and metabolic stability. Optimized analogs, including the frontrunner compound S-WJM992, were shown to inhibit PfATP4-associated Na+-ATPase activity, gave rise to a metabolic signature consistent with PfATP4 inhibition, and displayed altered activities against parasites with mutations in PfATP4. Finally, S-WJM992 showed appreciableefficacy in a malaria mouse model and blocked gamete development preventing transmission to mosquitoes. Importantly, further optimization of the dihydroquinazolinone class is required to deliver a candidate with improved pharmacokinetic and risk of resistance profiles.

Graphical Abstract

Published in: ChemistrySelect, Volume9, Issue30, August 12, 2024, e202400574

DOI: 10.1002/slct.202400574

Authors: Nazir Uddin, Sudipta Roy [TCGLS Member], Sayantan Roy [TCGLS Member], Dipankar Paul, Geetanjali Basumatary, Gitish K. Dutta, Paresh Nath Chatterjee

Abstract: An alternative approach to synthesize bis-indolylmethanes (BIMs) via a unique p-toluenesulfonic acid (PTSA) catalyzed dual C_sp3−C_sp2 bond-breaking reaction has been reported here. In the reported protocol, 1,3,5-trimethoxybenzene (TMB), an electron-rich and sterically bulky arene, acts as a carbon-based leaving group which can be recovered after the completion of the reaction. In this process, several BIMs of various indole derivatives can be synthesized from symmetrical triarylmethanes (TRAMs) containing bis-TMB motifs. By modifying the reaction conditions, we could control the sequential bond cleavage of two C_sp3−C_sp2 bonds in starting TRAM.

Graphical Abstract A double C−C bond-cleaving reaction under mild PTSA-catalyzed conditions to synthesize bis-indolylmethanes is reported. 1,3,5-Trimethoxybenzene, which not only acts as a good leaving group but also is recoverable and reusable. The conceptually unique method explores by-product re-utilization in chemical synthesis, making the current protocol an illustration towards sustainability.

Published in: Journal of Medicinal Chemistry, ASAP
DOI: 10.1021/acs.jmedchem.4c01154

Authors: Godwin AkpekoDziwornu,Donald Seanego,Stephen Fienberg,Monica Clements,Jasmin Ferreira, Venkata S. Sypu, Sauvik Samanta, Ashlyn D. Bhana, Constance M. Korkor,Larnelle F. Garnie, Nicole Teixeira, Kathryn J. Wicht, Dale Taylor, Ronald Olckers, Mathew Njoroge,Liezl Gibhard, Nicolaas Salomane, Sergio Wittlin, Rohit Mahato(TCGLS Member), Arnish Chakraborty(TCGLS Member), Nicole Sevilleno,Rachael Coyle, Marcus C. S. Lee, Luiz C. Godoy, Charisse Flerida Pasaje, Jacquin C. Niles, Janette Reader, Mariette van der Watt, Lyn-Marié Birkholtz, Judith M. Bolscher,Marloes H. C. de Bruijni, Lauren B. Coulson, Gregory S. Basarab, Sandeep R. Ghorpade,and Kelly Chibale.

Abstract: Structure−activity relationship studies of 2,8-disubstituted-1,5-naphthyridines, previously reported as potentinhibitors of Plasmodium falciarum (Pf) phosphatidylinositol-4-kinase β (PI4K), identified 1,5-naphthyridines with basic groups at8-position, which retained Plasmodium PI4K inhibitory activity butswitched primary mode of action to the host hemoglobindegradation pathway through inhibition of hemozoin formation.These compounds showed minimal off-target inhibitory activityagainst the human phosphoinositide kinases and MINK1 andMAP4K kinases, which were associated with the teratogenicity andtesticular toxicity observed in rats for the Pf PI4K inhibitor clinicalcandidate MMV390048. A representative compound from theseriesretained activity against field isolates and lab-raised drug-resistant strains of Pf. It was efficacious in the humanized NSG mousemalaria infection model at a single oral dose of 32 mg/kg. This compound wasnonteratogenic in the zebrafish embryo model ofteratogenicity and has a low predicted human dose, indicating that this series has the potential to deliver a preclinical candidate formalaria.

Authors: Pati, Tanmay K.; Molla, Sabir Ali; Ghosh, Narendra Nath; Kundu, Mrinalkanti(TCGLS Member); Ajarul, Sk; Maity, Pradip ; Khamrai, Uttam(TCGLS Member); Maiti, Dilip K.

Abstract: N-substituted 2-pyridones as an N,O-directing group for selective C(sp²)-H activated thiolation, selenylation and sulfonamidation of ortho C-H bonds of benzamides was demonstrated . This method utilizes a cost-effective Cu(II)-salt catalyst instead of precious metal catalysts, achieving high yields, including gram-scale synthesis and excellent functional group tolerance. This protocol applied to access 30 different compounds with high yields, demonstrating thiolation of fluorine-substituted benzamides as well. D. functional theory (DFT) calculations support the mechanism, including acetate-supported concerted metalation deprotonation (CMD) steps and the unique role of DMSO solvent. The facile synthesis of pharmaceutically important sulfonamides and other compounds highlights the method′s potential in chem. and medicinal chem.

Published in: eBioMedicine

Volume 102, April 2024, 105073

Authors: Benjamin Blasco, Soojin Jang, Hiroki Terauchi, Naoki Kobayashi, Shuichi Suzuki, Yuichiro Akao, Atsuko Ochida, Nao Morishita, Terufumi Takagi, Hiroyuki Nagamiya, Yamato Suzuki, Toshiaki Watanabe, Hyunjung Lee, Sol Lee, David Shum, Ahreum Cho, Dahae Koh, Soonju Park, Honggun Lee, Kideok Kim, Henni-Karoliina Ropponen, Renata Maria Augusto da Costa, Steven Dunn, Sunil Ghosh(TCGLS MEMBER), Peter Sjö, Laura J.V. Piddock

Abstract: The current pipeline for new antibiotics fails to fully address the significant threat posed by drug-resistant Gram-negative bacteria that have been identified by the World Health Organization (WHO) as a global health priority. New antibacterials acting through novel mechanisms of action are urgently needed. We aimed to identify new chemical entities (NCEs) with activity against Klebsiella pneumoniae and Acinetobacter baumannii that could be developed into a new treatment for drug-resistant infections. METHODS: We developed a high-throughput phenotypic screen and selection cascade for generation of hit compounds active against multidrug-resistant (MDR) strains of K. pneumoniae and A. baumannii. We screened compound libraries selected from the proprietary collections of three pharmaceutical companies that had exited antibacterial drug discovery but continued to accumulate new compounds to their collection. Compounds from two out of three libraries were selected using “eNTRy rules” criteria associated with increased likelihood of intracellular accumulation in Escherichia coli. FINDINGS: We identified 72 compounds with confirmed activity against K. pneumoniae and/or drug-resistant A. baumannii. Two new chemical series with activity against XDR A. baumannii were identified meeting our criteria of potency (EC₅₀ ≤50 μM) and absence of cytotoxicity (HepG2 CC₅₀ ≥100 μM and red blood cell lysis HC₅₀ ≥100 μM). The activity of close analogues of the two chemical series was also determined against A. baumannii clinical isolates. INTERPRETATION: This work provides proof of principle for the screening strategy developed to identify NCEs with antibacterial activity against multidrug-resistant critical priority pathogens such as K. pneumoniae and A. baumannii. The screening and hit selection cascade established here provide an excellent foundation for further screening of new compound libraries to identify high quality starting points for new antibacterial lead generation projects. FUNDING: BMBF and GARDP.

Published in: Nat Commun 15, 937 (2024).

DOI: 10.21203/rs.3.rs-3198291/v1

Authors: Stanley C. Xie, Yinuo Wang, Craig J. Morton, Riley D. Metcalfe, Con Dogovski, Charisse Flerida A. Pasaje, Elyse Dunn, Madeline R. Luth, KrittikornKumpornsin, Eva S. Istvan, Joon Sung Park, Kate J. Fairhurst, NutpakalKetprasit, Tomas Yeo, Okan Yildirim, Mathamsanqa N. Bhebhe, Dana M. Klug, Peter J. Rutledge, Luiz C. Godoy, Sumanta Dey, Mariana Laureano De Souza, Jair L. Siqueira-Neto, Yawei Du, Tanya Puhalovich, Mona Amini, Gerry Shami, DuangkamonLoesbanluechai, Shuai Nie, Nicholas Williamson, Gouranga P. Jana(TCGLS MEMBER), Bikash C. Maity(TCGLS MEMBER), Patrick Thomson, Thomas Foley, Derek S. Tan, Jacquin C. Niles, Byung Woo Han, Daniel E. Goldberg, Jeremy Burrows, David A. Fidock, Marcus C. S. Lee, Elizabeth A. Winzeler, Michael D. W. Griffin, Matthew H. Todd & Leann Tilley.

Abstract: Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism.

Published in: SCIENCE, 23 Nov 2023, Vol 382, Issue 6673, pp. 935-940

Authors: GANESH M. NAWKAR, MARTINA, ANUPAMA GOYAL (TCGLS MEMBER), EMANUEL SCHMID-SIEGERT, JÉRÉMY FLEURY, ANTONIO MUCCIOLO, DAMIEN DE BELLIS, MARTINE TREVISAN, ANDREAS, AND CHRISTIAN FANKHAUSER

DOI: https://www.science.org/doi/10.1126/science.adh9384

Abstract: In plants, light direction is perceived by the phototropin photoreceptors, which trigger directional growth responses known as phototropism. The formation of a phototropin activation gradient across a photosensitive organ initiates this response. However, the optical tissue properties that functionally contribute to phototropism remain unclear. In this work, we show that intercellular air channels limit light transmittance through various organs in several species. Air channels enhance light scattering in Arabidopsis hypocotyls, thereby steepening the light gradient. This is required for an efficient phototropic response in Arabidopsis and Brassica. We identified an embryonically expressed ABC transporter required for the presence of air channels in seedlings and a structure surrounding them. Our work provides insights into intercellular air space development or maintenance and identifies a mechanism of directional light sensing in plants.

Published in: J. Org. Chem

DOI: 10.1021/acs.joc.3c01852

Authors: Arun Kumar Hajra(TCGLS Member), Prasanjit Ghosh*, Priyanka Paul(TCGLS Member), Mrinalkanti Kundu*(TCGLS Member), and Sajal Das*

Abstract: An operationally simple and efficient protocol for copper(II)-mediated, picolinamido-directed C8–H sulfonamidation of 1-naphthylamine derivatives with various sulfonamides has been developed. Remarkably, this cross-dehydrogenative C–H/H–N coupling reaction exhibits a broad substrate scope with excellent functional group tolerance, is scalable, and enables an expeditious route to a library of unsymmetrical N-arylated sulfonamides in good to excellent yields with exclusive site selectivity.

Published in: ACS Medicinal Chemistry Letters

DOI: 10.1021/acsmedchemlett.3c00369

Authors: Nicolas Bosc, Eloy Felix, J. Mark F. Gardner, James Mills, Martijn Timmerman, Dennis Asveld,Kim Rensen, Partha Mukherjee(TCGLS Member), Rishi Das(TCGLS Member), Elodie Chenu, Dominique Besson, Jeremy N. Burrows,James Duffy, Benoît Laleu, Eric M. Guantai, and Andrew R. Leach

Abstract: Efforts to tackle malaria must continue for a disease that threatens half of the global population. Parasite resistance to current therapies requires new chemotypes that are able to demonstrate effectiveness and safety. Previously, we developed a machine-learning-based approach to predict compound antimalarial activity, which was trained on the compound collections of several organizations. The resulting prediction platform, MAIP, was made freely available to the scientific community and offers a solution to prioritize molecules of interest in virtual screening and hit-to-lead optimization. Here, we experimentally validate MAIP and demonstrate how the approach was used in combination with a robust compound selection workflow and a recently introduced innovative high-throughput screening (HTS) cascade to select and purchase compounds from a public library for subsequent experimental screening. We observed a 12-fold enrichment compared with a randomly selected set of molecules, and the eight hits we ultimately selected exhibit good potency and absorption, distribution, metabolism, and excretion (ADME) profiles.