Archives: Publication

Published in : European Journal of Medicinal Chemistry Volume 280, 15 December 2024, 116921

DOI : 10.1016/j.ejmech.2024.116921

Authors : Jon Kyle Awalt, Wenyin Su, William Nguyen, Katie Loi, Kate E. Jarman, Jocelyn S. Penington, Saishyam Ramesh, Kate J. Fairhurst, Tomas Yeo, Heekuk Park, Anne-Catrin Uhlemann, Bikash ChandraMaity [TCGLS Member], Nirupam De [TCGLS Member], Partha Mukherjee [TCGLS Member], Arnish Chakraborty [TCGLS Member], Alisje Churchyard, Mufuliat T. Famodimu, MichaelJ. Delves, Jake Baum, Nimisha Mittal…Brad E. Sleebs

Abstract : Drug resistance against antimalarials is rendering them increasingly ineffective and so there is a need for the development of new antimalarials. To discover new antimalarial chemotypes a phenotypic screen of the Janssen Jumpstarter library against the P. falciparum asexual stage was undertaken, uncovering the cyclopropyl carboxamide structural hit class. Structure-activity analysis revealed that each structural moiety was largely resistant to change, although small changes led to the frontrunner compound, WJM280, which has potent asexual stage activity (EC₅₀ 40 nM) and no human cell cytotoxicity. Forward genetics uncovered that cyclopropyl carboxamide resistant parasites have mutations and an amplification in the cytochrome b gene. Cytochrome b was then verified as the target with profiling against cytochrome b drug-resistant parasites and a mitochondrial oxygen consumption assay. Accordingly, the cyclopropyl carboxamide class was shown to have slow-acting asexual stage activity and activity against male gametes and exoerythrocytic forms. Enhancing metabolic stability to attain efficacy in malaria mouse models remains a challenge in the future development of this antimalarial chemotype.

Published in: ACS Pharmacol. Transl. Sci. 2024, 7, 9, 2662–2676

Authors: Subhasis Roy (TCGLS Member), Monali Chakrabarti(TCGLS Member), Trisha Mondal(TCGLS Member), Tapas Kumar Das(TCGLS Member), Tonmoy Sarkar(TCGLS Member), Sebak Datta(TCGLS Member), Mrinalkanti Kundu(TCGLS Member), Manish Banerjee(TCGLS Member), Onkar Prakash Kulkarni

Abstract: The role of autotaxin (ATX)-lysophosphatidic acid (LPA) is yet to be explored in the context of liver cirrhosis and associated encephalopathy. Our objective of this study was to evaluate the role of an ATX inhibitor in biliary cirrhosis and associated hepatic encephalopathy in rats. The preliminary investigation revealed significant impairment in liver function, which eventually led to the development of hepatic encephalopathy. Interestingly, LPA levels were significantly increased in the plasma, liver, and brain of rats following bile duct ligation. Subsequently, we tested the efficacy of an ATX inhibitor, CBT-295, in bile duct-induced biliary cirrhosis and neuropsychiatric symptoms associated with hepatic encephalopathy. CBT-295 showed good oral bioavailability and favorable pharmacokinetic properties. CBT-295 exhibited a significant reduction in inflammatory cytokines like TGF-β, TNF-α, and IL-6 levels, also reduced bile duct proliferation marker CK-19, and lowered liver fibrosis, as evident from reduced collagen deposition. The reversal of liver fibrosis with CBT-295 led to a reduction in blood and brain ammonia levels. Furthermore, CBT-295 also reduced neuroinflammation induced by ammonia, which is characterized by a significant reduction in brain cytokine levels. It improved neuropsychiatric symptoms such as locomotor activities, cognitive impairment, and clinical grading scores associated with hepatic encephalopathy. The improvement in hepatic encephalopathy observed with the ATX inhibitor could be the result of its hepatoprotective action and its ability to attenuate neuroinflammation. Therefore, inhibition of ATX-LPA signaling can be a multifactorial approach for the treatment of chronic liver diseases.

Graphical Abstract:

Published in: International Journal of Biological MacromoleculesVolume 278, Part 1, October 2024, 134651

Authors: ShayeriChatterjee Ganguly, Beduin Mahanti, Soumya Ganguly (TCGLS Member), Subhabrota Majumdar

Abstract: Garcinia indica, known as kokum, has been extensively researched for its therapeutic potential. Among the wide variety of phytoconstituents, garcinol is the most efficacious, holding anti-inflammatory, anti-cancer, and anti-diabetic properties. Hydrophobicity and a certain level of toxicity have constrained the drug’s application and necessitated a modified dosage form design. The drug has been well explored in the form of extracts but bears very limited application in dosage forms. These prompted in implementation of protein polymers, due to non-toxicity, biocompatibility, and biodegradability. BSA encapsulates the drug, by the desolvation method. The unavailability of past exploration of garcinol with protein polymer accelerated the novelty of this study, to improve the solubility and bioavailability of the drug, modify the drug release kinetics, and ascertain the effectiveness of the NPs to combat inflammation in-vitro. NPs were characterized and satisfactory outcomes were retrieved in terms of all characterizations. The drug release studies depicted a sustained release of up to 85 % over 16 h, ensuring that garcinol can be modulated to give a desired scale of modified release. In vitro cellular uptake studies suggested a substantial uptake of NPs in cell lines and its effectiveness to mitigate inflammation was affirmed by in-vitro anti-inflammatory studies, using ELISA.

Published in: J. Org. Chem. 2024, 89, 16, 11467–11479

Authors: Tapas Kumar Das (TCGLS Member), Prasanjit Ghosh, Shibaji Ghosh, Sajal Das

Abstract: Selective installation of halo and nitro groups in heterocyclic backbone through a transition-metal-catalyzed C–H bond activation strategy is immensely alluring to access high-value scaffolds. Here in, we disclosed N-pyrimidyl-directed assisted palladium(II)-catalyzed C(sp²)8–H halogenation and nitration of substituted 4-quinolone derivatives in the presence of N-halosuccinimide and tert-butyl nitrite, respectively, offering structurally diversified 8-halo/nitro-embedded 4-quinolone frameworks in high yields. Mechanistic studies indicated that the reaction follows an organometallic pathway with a reversible C–H metalation step. This operationally simple protocol is scalable with a broad substrate scope and excellent functional group compatibility. Moreover, the postdiversifications of the synthesized derivatives are also showcased to ensure the synthetic versatility of the methodology.

Grapical Abstract:

Published in: Microbial drug resistance (Larchmont, N.Y.)

Journal; Article

2024

Authors:  Soumitra Moulick (TCGLS Member) and Dijendra Nath Roy

Abstract: The rise in antibiotic resistance among bacterial pathogens, particularly Staphylococcus aureus, has become a critical global health issue, necessitating the search for novel antimicrobial agents. S. aureus uses various mechanisms to resist antibiotics, including the activation of efflux pumps, biofilm formation, and enzymatic modification of drugs. This study explores the potential of baicalein, a bioflavonoid from Scutellaria baicalensis, in modulating tetracycline resistance in S. aureus by inhibiting efflux pumps. The synergistic action of baicalein and tetracycline was evaluated through various assays. The minimum inhibitory concentration (MIC) of baicalein and tetracycline against S. aureus was 256 and 1.0 μg/mL, respectively. Baicalein at 64 μg/mL reduced the MIC of tetracycline by eightfold, indicating a synergistic effect (fractional inhibitory concentration index: 0.375). Time–kill kinetics demonstrated a 1.0 log CFU/mL reduction in bacterial count after 24 hours with the combination treatment. The ethidium bromide accumulation assay showed that baicalein mediated significant inhibition of efflux pumps, with a dose-dependent increase in fluorescence. In addition, baicalein inhibited DNA synthesis by 73% alone and 92% in combination with tetracycline. It also markedly reduced biofilm formation and the invasiveness of S. aureus into HeLa cells by 52% at 64 μg/mL. These findings suggest that baicalein enhances tetracycline efficacy and could be a promising adjunct therapy to combat multidrug-resistant S. aureus infections.

Published in: ChemMedChem, Pages: e202400549, Journal; Article, 2024

DOI: 10.1002/cmdc.202400549

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

Abstract: The emergence of resistance against current antimalarial treatments has necessitated the need for the development of novel antimalarial chemotypes. Toward this goal, we recently optimised the antimalarial activity of the dihydroquinazolinone scaffold and showed it targeted PfATP4. Here, we deconstruct the lactam moiety of the tricyclic dihydroquinazolinone scaffold and investigate the structure-activity relationship of the truncated scaffold. It was shown that SAR between scaffolds was largely transferrable and generated analogues with potent asexual stage activity. Evaluation of the truncated analogues against PfATP4 mutant drug resistant parasite strains and in assays measuring PfATP4-associated ATPase activity demonstrated retention of PfATP4 as the molecular target. Analogues exhibited activity against both male and female gametes and multidrug resistant parasites. Limited efficacy of analogues in a P. berghei asexual stage mouse model was attributed to their moderate metabolic stability and low aqueous stability. Further development is required to address these attributes toward the potential use of the dihydroquinazolinone class in a curative and transmission blocking combination antimalarial therapy.

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.