Archives: Publication

Published in: Medical Oncology, January 2025

DOI: 10.1007/s12032-025-02605-8

Authors: Laavanya Das, Subhadip Das [TCGLS Member]

Abstract: Cancer is a major global health issue that is usually treated with multiple therapies, such as chemotherapy and targeted therapies like immunotherapy. Immunotherapy is a new and alternative approach to treating various types of cancer that are difficult to treat with other methods. Although immune checkpoint inhibitors have shown promise for long-term efficacy, they have limited effectiveness in common cancer types such as breast, prostate, and lung. Some patients do not respond to immunotherapy, while others develop resistance to the treatment over time, which is classified as primary or acquired resistance. Cancer immunotherapy, specifically immune checkpoint inhibitor-based resistance involves multiple factors such as genes, metabolism, inflammation, and angiogenesis. However, cutting-edge research has identified the mechanisms of immunotherapy resistance and possible solutions. Current research may improve biomarker identification and modify treatment strategies, which will lead to better clinical outcomes. This review provides a comprehensive discussion of the current mechanisms of immunotherapy resistance, related biomarker modulation, and strategies to overcome resistance.

The major components of tumour microenvironment.

Published in: Synthesis, January 2025

DOI: 10.1055/s-0040-1720160

Authors: Manna, Priyadarshi [TCGLS Member]; Chatterjee, Arunima [TCGLS Member]; Kundu, Mrinalkanti [TCGLS Member]; Rao, G. Prabhakar [TCGLS Member]; Mukherjee, Rusmita [TCGLS Member]; Podder, Swarnali [TCGLS Member]; Datta, Bandita; Adhikari, Susanta

Abstract: Arylamines are essential building blocks that are found in biol. important substances, agrochems., and natural products. One of the C-N bond formation methods that is conveniently step- and atom-economical is the C-H bond activated amination process. We divulge an operationally simple and general method using 3-amino-1-methyl-1H-pyridin-2-one (AMP) as inbuilt directing group (DG) for additive-free, copper(II)-catalyzedorthoamination of β-C(sp²)-H bonds of arenes and heteroarenes. Notably, this cross dehydrogenative amination reaction exhibits a broad scope regarding amine coupling partners, including heterocyclic amines, secondary aliphatic amines, and cyclic amides, with exclusive site selectivity and excellent functional group tolerance. Moreover, implementing this methodol., we could also synthesize medicinally important compounds to showcase the suitability of this inbuilt DG for late-stage functionalization.

Published in: Journal of Medicinal Chemistry

J. Med. Chem. 2025, 68, 590−637

DOI: 10.1021/acs.jmedchem.4c02394

AuthorsZhe Nie, Roger Bonnert, Jet Tsien, Xiaoyi Deng, Christopher Higgs, Farah El Mazouni, Xiaoyu Zhang,Renzhe Li, Nhi Ho, Victoria Feher, Janet Paulsen, David M. Shackleford, KasiramKatneni, Gong Chen,Alice C. F. Ng, Mitchell McInerney, Wen Wang, Jessica Saunders, Daniel Collins, Dandan Yan, Peng Li,Michael Campbell, Rahul Patil, Atanu Ghoshal[TCGLS Member], Pallab Mondal[TCGLS Member], Abhijit Kundu[TCGLS Member], Rajesh Chittimalla,Muralikumar Mahadeva, Sreekanth Kokkonda, John White, Rishi Das[TCGLS Member], Partha Mukherjee[TCGLS Member],Iñigo Angulo-Barturen, María Belén Jiménez-Díaz, Robert Malmstrom, Morgan Lawrenz,Agustina Rodriguez-Granillo, Pradipsinh K. Rathod, Diana R. Tomchick, Michael J. Palmer, Benoît Laleu,Tian Qin, Susan A. Charman,* and Margaret A. Phillips*

Abstract:Malaria remains a serious global health challenge, yet treatment and control programs are threatened by drugresistance. Dihydroorotate dehydrogenase (DHODH) was clinically validated as a target for treatment and prevention of malariathrough human studies with DSM265, but currently no drugs against this target are in clinical use. We used structure-basedcomputational tools including free energy perturbation (FEP+) to discover highly ligand efficient, potent, and selective pyrazole-based Plasmodium DHODH inhibitors through a scaffold hop from a pyrrole-based series. Optimized pyrazole-based compoundswere identified with low nM-to-pM Plasmodium falciparum cell potency and oral activity in a humanized SCID mouse malariainfection model. The lead compound DSM1465 is more potent and has improved absorption, distribution, metabolism andexcretion/pharmacokinetic (ADME/PK) properties compared to DSM265 that support the potential for once-monthlychemoprevention at a low dose. This compound meets the objective of identifying compounds with potential to be used formonthly chemoprevention in Africa to support malaria elimination efforts.

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