Collaborative Virtual Screening Identifies a 2-Aryl-4-aminoquinazoline Series with Efficacy in an In Vivo Model of Trypanosoma cruzi Infection

Authors: Tawaraishi, Taisuke; Ochida, Atsuko; Akao, Yuichiro; Itono, Sachiko; Kamaura, Masahiro; Akther, Thamina; Shimada, Mitsuyuki; Canan, Stacie; Chowdhury, Sanjoy (TCGLS Member); Cao, Yafeng; Condroski, Kevin ; Engkvist, Ola ; Francisco, Amanda; Ghosh, Sunil (TCGLS Member); Kaki, Rina; Kelly, John M.; Kimura, Chiaki; Kogej, Thierry; Nagaoka, Kazuya; Naito, Akira; Pairaudeau, Garry; Radu, Constantin; Roberts, Ieuan; Shum, David; Watanabe, Nao-aki; Xie, Huanxu; Yonezawa, Shuji; Yoshida, Osamu; Yoshida, Ryu; Mowbray, Charles ; Perry, Benjamin

Publication: Journal of Medicinal Chemistry (2023), 66(2), 1221-1238

Abstract: Probing multiple proprietary pharmaceutical libraries in parallel via virtual screening allowed rapid expansion of the structure-activity relationship (SAR) around hit compounds with moderate efficacy against Trypanosoma cruzi, the causative agent of Chagas Disease. A potency-improving scaffold hop, followed by elaboration of the SAR via design guided by the output of the phenotypic virtual screening efforts, identified two promising hit compounds 54 and 85, which were profiled further in pharmacokinetic studies and in an in-vivo model of T. cruzi infection. Compound 85 demonstrated clear reduction of parasitemia in the in-vivo setting, confirming the interest in this series of 2-(pyridin-2-yl)quinazolines as potential anti-trypanosome treatments.

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Exploring a Tetrahydroquinoline Antimalarial Hit from the Medicines for Malaria Pathogen Box and Identification of its Mode of Resistance as PfeEF2

Dr. Benoît Laleu,Kelly Rubiano,Tomas Yeo,Irene Hallyburton,Dr. Mark Anderson,Benigno Crespo-Fernandez,Dr. Francisco-Javier Gamo,Dr. Yevgeniya Antonova-Koch,Dr. Pamela Orjuela-Sanchez,Dr. Sergio Wittlin,Dr. Gouranga P. Jana (TCGLS Member),Dr. Bikash C. Maity (TCGLS Member),Elodie Chenu,Dr. James Duffy,Dr. Peter Sjö,Dr. David Waterson,Prof. Elizabeth Winzeler,Dr. Eric Guantai,Prof. David A. Fidock,Dr. Thomas G. Hansson

Publication: ChemMedChem, e202200393

Abstract:  Toolkit expansion: We report an exploration of the antimalarial compound MMV692140. The mode of resistance was identified as PfeEF2. The structural motif was explored in a chemistry program, resulting in the identification of MMV1919557, an analog with significantly improved antimalarial potency. This new series could provide a tool to further understand the potential of PfeEF2 as a target for malaria treatment

New antimalarial treatments with novel mechanism of action are needed to tackle Plasmodium falciparum infections that are resistant to first-line therapeutics. Here we report the exploration of MMV692140 (2) from the Pathogen Box, a collection of 400 compounds that was made available by Medicines for Malaria Venture (MMV) in 2015. Compound 2 was profiled in in vitro models of malaria and was found to be active against multiple life-cycle stages of Plasmodium parasites. The mode of resistance, and putatively its mode of action, was identified as Plasmodium falciparum translation elongation factor 2 (PfeEF2), which is responsible for the GTP-dependent translocation of the ribosome along mRNA. The compound maintains activity against a series of drug-resistant parasite strains. The structural motif of the tetrahydroquinoline (2) was explored in a chemistry program with its structure-activity relationships examined, resulting in the identification of an analog with 30-fold improvement of antimalarial asexual blood stage potency.

Synthesis, anti-cancer activity and molecular docking studies of new nicotinamide containing EP4 antagonists

Md. Akram Ali (TCGLS Member), Rajib Chakraborty (TCGLS Member), Susanta Kumar Mondal (TCGLS Member). Supriya Bhunia, Sabyasachi Chakraborty (TCGLS Member), Subhas Samanta, Sonali Rudra (TCGLS Member)

Publication: Journal of Molecular Structure Volume 1260, 15 July 2022, 132730

Abstract: Selective binding of the pleiotropic lipid mediator prostanoid Prostaglandin E2 (PGE2) towards the G-protein coupled EP4 receptor has been studied extensively for inflammatory and hyperalgesia models and has been implicated to have significant potential for the treatment of various forms of cancers. Interest of nicotinamides as EP4 antagonists for oncology research, led us to synthesize a small set of molecules using the nicotinamide derivative AAT-008 (1) as our starting point for design. Subtle changes by replacing the hydrogen bond accepting bi-aryl-ether moiety in (1) to hydrogen bond donating bi-aryl-amino moiety and thereafter modifications on the substituents in the bi-aryl ring systems, carboxyl and the amino groups enabled us to identify a modestly potent new EP4 antagonist compound 14 with IC50 = 0.543 ± 0.148 μM (n = 6). Compound 14 was found to be stable in ADME assays and had reasonably good solubility. The interplay of electronic parameters such as lipohilicity and polarity of the compounds did not seem to play a significant role in deriving the EP4 antagonism potency for these compounds. Thus, molecular docking studies were carried out to understand the structure activity relationships (SAR). The trend in activity range of the synthesized compounds and the lower EP4 activity of compound 14 in contrast to compound 1 was explained with aid of molecular docking studies that supported our experimental potency results also. Preliminary screening of compounds 1 and 14 for oncology showed weak activity at a modest dose of 500 μM in breast cancer cells (MDA-MB-231) and moderately significant activity in colon cancer cells (HCT-116) cytotoxicity assays. Since, there was relatively higher cytotoxic activity in colon cancer cell lines, the cytotoxic effects of these two compounds were further evaluated under PGE2 induced conditions in two colon cancer cell lines: HCT-116 cells (IC50 values of 46 µM and 50 µM for compounds 1 and 14, respectively) and HT-29 cells (IC50 values of 37 µM and 4.5 µM for compounds 1 and 14, respectively) which signifies the possible relevance of the prostanoid inhibition pathway and its interference through the PGE2 induced oncogenic pathway.

Bioinspired Synthesis of Pinoxaden Metabolites Using a Site-Selective C–H Oxidation Strategy

Sameer Tyagi, Bruce P. McKillican, Tolani K. Salvador, Moses G. Gichinga, William J. Eberle, Russell Viner, Katarina J. Makaravage, Trey S. Johnson, C. Adam Russell, and Subho Roy (TCGLS Member)

Publication: J. Org. Chem. 2022, 87, 9, 6202–6211

Abstract: A bioinspired synthesis of Pinoxaden metabolites 2–5 is described herein. A site-selective C–H oxidation strategy validated by density functional theory (DFT) calculations was devised for preparing metabolites 2–4. Oxidation of the benzylic C–H bond in tertiary alcohol 7 using K2S2O8 and catalytic AgNO3 formed the desired metabolite 2 that enabled access to metabolites 3 and 4 in a single step. Unlike most metal/persulfate-catalyzed transformations reported for the C–C and C–O bond formation reactions wherein the metal acts as a catalyst, we propose that Ag(I)/K2S2O8 plays the role of an initiator in the oxidation of intermediate 7 to 2. Metabolite 2 was subjected to a ruthenium tetroxide-mediated C–H oxidation to form metabolites 3 and 4 as a mixture that were purified to isolate pure standards of these metabolites. Metabolite 5 was synthesized from readily available advanced intermediate 9via a House–Meinwald-type rearrangement in one step using a base.

Diastereo- and regioselective petasis aryl and allyl boration of ninhydrins towards synthesis of functionalized indene-diones and dihydrobenzoindeno-oxazin-ones

Ayon Sengupta (TCGLS Member), Suvendu Maity, Pinaki Saha, Prasanta Ghosh, Sonali Rudra (TCGLS Member), Chhanda Mukhopadhyay

Publication: Mol Divers. 2022 Aug 1. doi: 10.1007/s11030-022-10496-4. Online ahead of print

Abstract: Petasis aryl and allyl borations were accomplished using substituted ninhydrins, boronic acids or 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and 1,2-aminophenols in Hexafluoroisopropanol (HFIP) without any catalysts to synthesize different aryl and allyl derivatives of ninhydrins. The nature of substitution in the boronic acids and 1,2-amino phenols was the key factor in determining the diastereo-regioselectivity and the type of product distributions. The products were isolated and characterized by HMBC, HSQC, 1H, 13C NMR experiments and X-ray single crystallographic analysis. A probable reaction pathway involves in situ formation of acyclic and cyclic ninhydrin-amino alcohol adducts, with the positioned hydroxyl group determining the stereo-regioselective outcome via tetracoordinated boron intermediates. A metal free diastereo- and regioselective Petasis aryl and allyl boration of ninhydrins

Identification of 5-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine as novel orally bioavailable and metabolically stable antimalarial compound for further exploration

Kundu Mrinalkanti (TCGLS Member); Dutta Aditi (TCGLS Member); Mal Sajal K (TCGLS Member); Karmakar Shouvik (TCGLS Member); Mandal Aritra (TCGLS Member); Mondal Susanta K (TCGLS Member); Kumar Sanjay (TCGLS Member); Saha Soumya (TCGLS Member); Pradhan Subhankar (TCGLS Member); Sarkar Ratul (TCGLS Member); Chakrabarti Monali (TCGLS Member); Malik Pradip K (TCGLS Member); Banerjee Manish (TCGLS Member); Roy Kuldeep K

Publication: Chemical biology & drug design, ASAP

Abstract: Malaria continues to be a significant public health problem threatened by the emergence and spread of resistance to artemisinin-based combination therapies and marked half a million deaths in 2016. A new imidazopyridine chemotype has been envisaged through scaffold-hopping approach combined with docking studies for putative binding interactions with Plasmodium falciparum phosphatidylinositol-4-kinase (PfPI4K) target. The docking results steered to the synthesis of compound 1 [5-(3-(methylsulfonyl)phenyl)-3-(4-(methylsulfonyl)phenyl)-3H-imidazo[4,5-b]pyridine] followed by the in vitro screening for antiplasmodial activity and ADME-PK studies. Combined with potent antimalarial activity of compound 1 (Pf3D7 IC50 = 29 nM) with meager in vitro intrinsic clearance, moderate plasma-protein binding and acceptable permeability, compound 1 displayed sustained exposure and high oral bioavailability in mice and can thus have the potential as next generation PI4K inhibitor for in vivo studies.

Organocatalytic synthesis of (Het)biaryl scaffolds via photoinduced intra/intermolecular C(sp2)–H arylation by 2-pyridone derivatives

Tapas Kumar Das (TCGLS Member), Mrinalkanti Kundu (TCGLS Member), Biswajit Mondal (TCGLS Member), Prasanjit Ghosh and Sajal Das
Organic and Biomolecular Chemistry 2022,20, 208-218 (Published on 30th Nov 2021)

Abstract: A unique N,O-bidentate ligand 6-oxo-1,6-dihydro-pyridone-2-carboxylic acid dimethylamide (L1) catalyzed direct C(sp2)–H (intra/intermolecular) arylation of unactivated arenes has been developed to expedite access to (Het)biaryl scaffolds under UV-irradiation at room temperature. The protocol tolerated diverse functional groups and substitution patterns, affording the target products in moderate to excellent yields. Mechanistic investigations were also carried out to better understand the reaction pathway. Furthermore, the synthetic applicability of this unified approach has been showcased via the construction of biologically relevant 4-quinolone, tricyclic lactam and sultam derivatives.

Structure-based discovery of (S)-2-amino-6-(4-fluorobenzyl)-5,6,11,11a-tetrahydro-1H-imidazo[1′,5′:1,6]pyrido[3,4-b]indole-1,3(2H)-dione as low nanomolar, orally bioavailable autotaxin inhibitor

Ashis Roy (TCGLS Member), Tonmoy Sarkar (TCGLS Member), Sebak Datta (TCGLS Member), Arup Maiti (TCGLS Member), Monali Chakrabarti (TCGLS Member), Trisha Mondal (TCGLS Member), Chaitali Mondal (TCGLS Member), Apurba Banerjee (TCGLS Member), Subhasis Roy (TCGLS Member), Soumen Mukherjee (TCGLS Member), Pragati Muley (TCGLS Member), Sabyasachi Chakraborty (TCGLS Member), Manish Banerjee (TCGLS Member), Mrinalkanti Kundu (TCGLS Member), Kuldeep K. Roy
Chemical Biology and Drug Design, Volume99, Issue3 March 2022 Pages 496-503 (Published on 24th Dec 2021)

Abstract: Inhibition of extracellular secreted enzyme autotaxin (ATX) represents an attractive strategy for the development of new therapeutics to treat various diseases and a few inhibitors entered in clinical trials. We herein describe structure-based design, synthesis, and biological investigations revealing a potent and orally bioavailable ATX inhibitor 1. During the molecular docking and scoring studies within the ATX enzyme (PDB-ID: 4ZGA), the S-enantiomer (Gscore = −13.168 kcal/mol) of the bound ligand PAT-494 scored better than its R-enantiomer (Gscore = −9.562 kcal/mol) which corroborated with the reported observation and analysis of the results suggested the scope of manipulation of the hydantoin substructure in PAT-494. Accordingly, the docking-based screening of a focused library of 10 compounds resulted in compound 1 as a better candidate for pharmacological studies. Compound 1 was synthesized from L-tryptophan and evaluated against ATX enzymatic activities with an IC50 of 7.6 and 24.6 nM in biochemical and functional assays, respectively. Further, ADME-PK studies divulged compound 1 as non-cytotoxic (19.02% cell growth inhibition at 20 μM in human embryonic kidney cells), metabolically stable against human liver microsomes (CLint = 15.6 μl/min/mg; T1/2 = 113.2 min) with solubility of 4.82 μM and orally bioavailable, demonstrating its potential to be used for in vivo experiments.

Facile and Scalable Methodology for the Pyrrolo[2,1-f][1,2,4]triazine of Remdesivir

Sarabindu Roy (TCGLS Member), Ajay Yadaw (TCGLS Member), Subho Roy (TCGLS Member), Gopal Sirasani (TCG GC Member), Aravind Gangu (TCG GC Member), Jack D. Brown (TCG GC Member), Joseph D. Armstrong III (TCG GC Member), Rodger W. Stringham, B. Frank Gupton, Chris H. Senanayake* (TCG GC Member), and David R. Snead*Organic Process Research and Development (Published on 07th Jan 2022)

Abstract: Pyrrolo[2,1-f][1,2,4]triazine (1) is an important regulatory starting material in the production of the antiviral drug remdesivir. Compound 1 was produced through a newly developed synthetic methodology utilizing simple building blocks such as pyrrole, chloramine, and formamidine acetate by examining the mechanistic pathway for the process optimization exercise. Triazine 1 was obtained in 55% overall yield in a two-vessel-operated process. This work describes the safety of the process, impurity profiles and control, and efforts toward the scale-up of triazine for the preparation of kilogram quantity.

Palladium-catalyzed directed synthesis of ortho-deuterated phenylacetic acid and analogues

Priyadarshi Manna (TCGLS Member); Mrinalkanti Kundu (TCGLS Member); Ashis Roy (TCGLS Member);Susanta Adhikari

Abstract: The synthesis of deuterium-labeled organic compounds is of increased interest, especially after the approval of deutetrabenazine by the Food and Drug Administration in 2014. The selective incorporation of deuterium in the place of hydrogen not only represents uniqueness in terms of a novel chemical class, but it also can improve the pharmacokinetic profiles of drug molecules while retaining potency and other parameters; thus, hydrogen–deuterium (H/D) exchange methods have been proven to be powerful additions in different areas of chemical science. In that regard, metal-catalyzed deuterium labeling via C–H activation mediated by a unique inbuilt directing group (DG) can play a significant role in the synthesis of novel deuterated chemical entities. In this context, herein, we divulge our results relating to Pd(II)-catalyzed deuterium incorporation (>97%) at the γ C(sp2)-position of pyridone-containing phenylacetic acid derivatives, where 3-amino-1-methyl-1H-pyridin-2-one (AMP) not only acts as an efficient N,O-directing group, but it also constitutes a part of the target molecules of medicinal importance. Our methodology, which has been optimized based on the effects of temperature, catalyst, time, and substrate scope, shows advantages over existing protocols, with non-selectivity or meager deuteration or the use of an expensive metal (catalytic or super stoichiometric) and a deuterated solvent, reported previously for the deuteration of phenylacetic acid and its derivatives. Moreover, towards our aim of synthesizing deuterium-labeled biologically relevant compounds, the gram scale synthesis of a deuterated analogue of biphenyl acetic acid (3), known to have activity against epileptic seizures, has also been successfully accomplished in high yields and with excellent isotope enrichment via implementing this protocol.