Design, synthesis, and biological evaluation of 5-(1H-indol-5-yl)isoxazole-3-carboxylic acids as novel xanthine oxidase inhibitors.

Xanthine oxidase (XO) is a key enzyme for the production of uric acid in the human body. XO inhibitors (XOIs) are clinically used for the treatment of hyperuricemia and gout, as they can effectively inhibit the production of uric acid. Previous studies indicated that both indole and isoxazole derivatives have good inhibitory effects against XO. Here, we designed and synthesized a novel series of N-5-(1H-indol-5-yl)isoxazole-3-carboxylic acids according to bioisosteric replacement and hybridization strategies. Among the obtained target compounds, compound 6c showed the best inhibitory activity against XO with an IC50 value of 0.13 µM, which was 22-fold higher than that of the classical antigout drug allopurinol (IC50 = 2.93 µM). Structure-activity relationship analysis indicated that the hydrophobic group on the nitrogen atom of the indole ring is essential for the inhibitory potencies of target compounds against XO. Enzyme kinetic studies proved that compound 6c acted as a mixed-type XOI. Molecular docking studies showed that the target compound 6c could not only retain the key interactions similar to febuxostat at the XO binding site but also generate some new interactions, such as two hydrogen bonds between the oxygen atom of the isoxazole ring and the amino acid residues Ser876 and Thr1010. These results indicated that 5-(1H-indol-5-yl)isoxazole-3-carboxylic acid might be an efficacious scaffold for designing novel XOIs and compound 6c has the potential to be used as a lead for further the development of novel anti-gout candidates.

Novel anthraquinone amide derivatives as potential glyoxalase-I inhibitors.

This study aimed to identify novel Glyoxalase-I (Glo-I) inhibitors with potential anticancer properties, focusing on anthraquinone amide-based derivatives. We synthesized a series of these derivatives and conducted in silico docking studies to predict their binding interactions with Glo-I. In vitro assessments were performed to evaluate the anti-Glo-I activity of the synthesized compounds. A comprehensive structure-activity relationship (SAR) analysis identified key features responsible for specific binding affinities of anthraquinone amide-based derivatives to Glo-I. Additionally, a 100 ns molecular dynamics simulation assessed the stability of the most potent compound compared to a co-crystallized ligand. Compound MQ3 demonstrated a remarkable inhibitory effect against Glo-I, with an IC50 concentration of 1.45 µM. The inhibitory potency of MQ3 may be attributed to the catechol ring, amide functional group, and anthraquinone moiety, collectively contributing to a strong binding affinity with Glo-I. Anthraquinone amide-based derivatives exhibit substantial potential as Glo-I inhibitors with prospective anticancer activity. The exceptional inhibitory efficacy of compound MQ3 indicates its potential as an effective anticancer agent. These findings underscore the significance of anthraquinone amide-based derivatives as a novel class of compounds for cancer therapy, supporting further research and advancements in targeting the Glo-I enzyme to combat cancer.

Perspectives and challenges in developing small molecules targeting purine nucleoside phosphorylase.

As a cytosolic enzyme involved in the purine salvage pathway metabolism, purine nucleoside phosphorylase (PNP) plays an important role in a variety of cellular functions but also in immune system, including cell growth, apoptosis and cancer development and progression. Based on its T-cell targeting profile, PNP is a potential target for the treatment of some malignant T-cell proliferative cancers including lymphoma and leukemia, and some specific immunological diseases. Numerous small-molecule PNP inhibitors have been developed so far. However, only Peldesine, Forodesine and Ulodesine have entered clinical trials and exhibited some potential for the treatment of T-cell leukemia and gout. The most recent direction in PNP inhibitor development has been focused on PNP small-molecule inhibitors with better potency, selectivity, and pharmacokinetic property. In this perspective, considering the structure, biological functions, and disease relevance of PNP, we highlight the recent research progress in PNP small-molecule inhibitor development and discuss prospective strategies for designing additional PNP therapeutic agents.

Identification of 1,3,4-Thiadiazolyl-Containing Thiazolidine-2,4-dione Derivatives as Novel PTP1B Inhibitors with Antidiabetic Activity.

Forty-one 1,3,4-thiadiazolyl-containing thiazolidine-2,4-dione derivatives (MY1-41) were designed and synthesized as protein tyrosine phosphatase 1B (PTP1B) inhibitors with activity against diabetes mellitus (DM). All synthesized compounds (MY1-41) presented potential PTP1B inhibitory activities, with half-maximal inhibitory concentration (IC50) values ranging from 0.41 ± 0.05 to 4.68 ± 0.61 µM, compared with that of the positive control lithocholic acid (IC50 = 9.62 ± 0.14 µM). The most potent compound, MY17 (IC50 = 0.41 ± 0.05 µM), was a reversible, noncompetitive inhibitor of PTP1B. Circular dichroism spectroscopy and molecular docking were employed to analyze the binding interaction between MY17 and PTP1B. In HepG2 cells, MY17 treatment could alleviate palmitic acid (PA)-induced insulin resistance by upregulating the expression of phosphorylated insulin receptor substrate and protein kinase B. In vivo, oral administration of MY17 could reduce the fasting blood glucose level and improve glucose tolerance and dyslipidemia in mice suffering from DM.

A ß-Carboline Derivate PAD4 Inhibitor Reshapes Neutrophil Phenotype and Improves the Tumor Immune Microenvironment against Triple-Negative Breast Cancer.

Triple-negative breast cancer is a highly aggressive and heterogeneous breast cancer subtype characterized by early metastasis, poor prognosis, and high recurrence. Targeting histone citrullination-mediated chromatin dysregulation to induce epigenetic alterations shows great promise in TNBC therapy. We report the synthesis, optimization, and evaluation of a novel series of ß-carboline-derived peptidyl arginine deiminase 4 inhibitors that exhibited potent inhibition of TNBC cell proliferation. The most outstanding PAD4 inhibitor, compound 28, hindered the PAD4-H3cit-NET signaling pathway and inhibited the growth of solid tumors and pulmonary metastatic nodules in the 4T1 in situ mouse model. Furthermore, 28 improved the tumor immune microenvironment by reshaping neutrophil phenotype, upregulating the proportions of dendritic cells and M1 macrophages, and reducing the amount of myeloid-derived suppressor cells. In conclusion, our work offered 28 as an efficacious PAD4 inhibitor that exerts a combination of conventional chemotherapy and immune-boosting effects, which represents a potential therapy strategy for TNBC.

Design, Synthesis, and Biological Activity of Novel Triketone-Containing Phenoxy Nicotinyl Inhibitors of HPPD.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a crucial target enzyme in albino herbicides. The inhibition of HPPD activity interferes with the synthesis of carotenoids, blocking photosynthesis and resulting in bleaching and necrosis. To develop herbicides with excellent activity, a series of 3-hydroxy-2-(6-substituted phenoxynicotinoyl)-2-cyclohexen-1-one derivatives were designed via active substructure combination. The title compounds were characterized via infrared spectroscopy, 1H and 13C nuclear magnetic resonance spectroscopies, and high-resolution mass spectrometry. The structure of compound III-17 was confirmed via single-crystal X-ray diffraction. Preliminary tests demonstrated that some compounds had good herbicidal activity. Crop safety tests revealed that compound III-29 was safer than the commercial herbicide mesotrione in wheat and peanuts. Moreover, the compound exhibited the highest inhibitory activity against Arabidopsis thaliana HPPD (AtHPPD), with a half-maximal inhibitory concentration of 0.19 µM, demonstrating superior activity compared with mesotrione (0.28 µM) in vitro. A three-dimensional quantitative structure-activity relationship study revealed that the introduction of smaller groups to the 5-position of cyclohexanedione and negative charges to the 3-position of the benzene ring enhanced the herbicidal activity. A molecular structure comparison demonstrated that compound III-29 was beneficial to plant absorption and conduction. Molecular docking and molecular dynamics simulations further verified the stability of the complex formed by compound III-29 and AtHPPD. Thus, this study may provide insights into the development of green and efficient herbicides.

Design, Synthesis, Antifungal Activity, and Action Mechanism of Pyrazole-4-carboxamide Derivatives Containing Oxime Ether Active Fragment As Succinate Dehydrogenase Inhibitors.

The dearomatization at the hydrophobic tail of the boscalid was carried out to construct a series of novel pyrazole-4-carboxamide derivatives containing an oxime ether fragment. By using fungicide-likeness analyses and virtual screening, 24 target compounds with theoretical strong inhibitory effects against fungal succinate dehydrogenase (SDH) were designed and synthesized. Antifungal bioassays showed that the target compound E1 could selectively inhibit the in vitro growth of R. solani, with the EC50 value of 1.1 µg/mL that was superior to that of the agricultural fungicide boscalid (2.2 µg/mL). The observations by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) demonstrated that E1 could reduce mycelial density and significantly increase the mitochondrial number in mycelia cytoplasm, which was similar to the phenomenon treated with boscalid. Enzyme activity assay showed that the E1 had the significant inhibitory effect against the SDH from R. solani, with the IC50 value of 3.3 µM that was superior to that of boscalid (7.9 µM). The mode of action of the target compound E1 with SDH was further analyzed by molecular docking and molecular dynamics simulation studies. Among them, the number of hydrogen bonds was significantly more in the SDH-E1 complex than that in the SDH-boscalid complex. This research on the dearomatization strategy of the benzene ring for constructing pyrazole-4-carboxamides containing an oxime ether fragment provides a unique thought to design new antifungal drugs targeting SDH.

Synthesis, In Silico and Kinetics Evaluation of N-(ß-d-glucopyranosyl)-2-arylimidazole-4(5)-carboxamides and N-(ß-d-glucopyranosyl)-4(5)-arylimidazole-2-carboxamides as Glycogen Phosphorylase Inhibitors.

Recently studied N-(ß-d-glucopyranosyl)-3-aryl-1,2,4-triazole-5-carboxamides have proven to be low micromolar inhibitors of glycogen phosphorylase (GP), a validated target for the treatment of type 2 diabetes mellitus. Since in other settings, the bioisosteric replacement of the 1,2,4-triazole moiety with imidazole resulted in significantly more efficient GP inhibitors, in silico calculations using Glide molecular docking along with unbound state DFT calculations were performed on N-(ß-d-glucopyranosyl)-arylimidazole-carboxamides, revealing their potential for strong GP inhibition. The syntheses of the target compounds involved the formation of an amide bond between per-O-acetylated ß-d-glucopyranosylamine and the corresponding arylimidazole-carboxylic acids. Kinetics experiments on rabbit muscle GPb revealed low micromolar inhibitors, with the best inhibition constants (Kis) of ~3-4 µM obtained for 1- and 2-naphthyl-substituted N-(ß-d-glucopyranosyl)-imidazolecarboxamides, 2b-c. The predicted protein-ligand interactions responsible for the observed potencies are discussed and will facilitate the structure-based design of other inhibitors targeting this important therapeutic target. Meanwhile, the importance of the careful consideration of ligand tautomeric states in binding calculations is highlighted, with the usefulness of DFT calculations in this regard proposed.

Evaluation of a panel of furochromenones as the activator and inhibitor of tyrosinase.

Tyrosinase is a copper-containing enzyme involved in the biosynthesis of melanin pigment. While the excess production of melanin causes hyperpigmentation of human skin, hypopigmentation results in medical conditions like vitiligo. Tyrosinase inhibitors could be used as efficient skin whitening agents and tyrosinase agonists could be used for enhanced melanin synthesis and skin protection from UV exposure. Among a wide range of tyrosinase-regulating compounds, natural and synthetic derivatives of furochromenones, such as 8-methoxypsoralen (8-MOP), are known to both activate and inhibit tyrosinase. We recently reported a synthetic approach to generate a variety of dihydrofuro[3,2-c]chromenones and furo[3,2-c]chromenones in a metal-free condition. In the present study, we investigated these compounds for their potential as antagonists or agonists of tyrosinase. Using fungal tyrosinase-based in vitro biochemical assay, we obtained one compound (3k) which could inhibit tyrosinase activity, and the other compound (4f) that stimulated tyrosinase activity. The kinetic studies revealed that compound 3k caused 'mixed' type tyrosinase inhibition and 4f stimulated the catalytic efficiency. Studying the mechanisms of these compounds may provide a basis for the development of new effective tyrosinase inhibitors or activators.

Synthesis of obovatol and related neolignan analogues as α-glucosidase and α-amylase inhibitors.

Diabetes mellitus is a metabolic disease characterized by hyperglycemia, which can be counteracted by the inhibition of α-glucosidase (α-Glu) and α-amylase (α-Amy), enzymes responsible for the hydrolysis of carbohydrates. In recent decades, many natural compounds and their bioinspired analogues have been studied as α-Glu and α-Amy inhibitors. However, no studies have been devoted to the evaluation of α-Glu and α-Amy inhibition by the neolignan obovatol (1). In this work, we report the synthesis of 1 and a library of new analogues. The synthesis of these compounds was achieved by implementing methodologies based on: phenol allylation, Claisen/Cope rearrangements, methylation, Ullmann coupling, demethylation, phenol oxidation and Michael-type addition. Obovatol (1) and ten analogues were evaluated for their in vitro inhibitory activity towards α-Glu and α-Amy. Our investigation highlighted that the naturally occurring 1 and four neolignan analogues (11, 22, 26 and 27) were more effective inhibitors than the hypoglycemic drug acarbose (α-Amy: 34.6 µM; α-Glu: 248.3 µM) with IC5O value of 6.2-23.6 µM toward α-Amy and 39.8-124.6 µM toward α-Glu. Docking investigations validated the inhibition outcomes, highlighting optimal compatibility between synthesized neolignans and both the enzymes. Concurrently circular dichroism spectroscopy detected the conformational changes in α-Glu induced by its interaction with the studied neolignans. Detailed studies through fluorescence measurements and kinetics of α-Glu and α-Amy inhibition also indicated that 1, 11, 22, 26 and 27 have the greatest affinity for α-Glu and 1, 11 and 27 for α-Amy. Surface plasmon resonance imaging (SPRI) measurements confirmed that among the compounds studied, the neolignan 27 has the greater affinity for both enzymes, thus corroborating the results obtained by kinetics and fluorescence quenching. Finally, in vitro cytotoxicity of the investigated compounds was tested on human colon cancer cell line (HCT-116). All these results demonstrate that these obovatol-based neolignan analogues constitute promising candidates in the pursuit of developing novel hypoglycemic drugs.

Design, Synthesis, and Biological Evaluation of Pyridazinone-Containing Derivatives As Novel Protoporphyrinogen IX Oxidase Inhibitor.

Protoporphyrinogen IX oxidase (PPO, E.C. 1.3.3.4) plays a pivotal role in chlorophyll biosynthesis in plants, making it a prime target for herbicide development. In this study, we conducted an investigation aimed at discovering PPO-inhibiting herbicides. Through this endeavor, we successfully identified a series of novel compounds based on the pyridazinone scaffold. Following structural optimization and biological assessment, compound 10ae, known as ethyl 3-((6-fluoro-5-(6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)benzo[d]thiazol-2-yl)thio)propanoate, emerged as a standout performer. It exhibited robust activity against Nicotiana tabacum PPO (NtPPO) with an inhibition constant (Ki) value of 0.0338 µM. Concurrently, we employed molecular simulations to obtain further insight into the binding mechanism with NtPPO. Additionally, another compound, namely, ethyl 2-((6-fluoro-5-(5-methyl-6-oxo-4-(trifluoromethyl)pyridazin-1(6H)-yl)benzo[d]thiazol-2-yl)thio)propanoate (10bh), demonstrated broad-spectrum and highly effective herbicidal properties against all six tested weeds (Leaf mustard, Chickweed, Chenopodium serotinum, Alopecurus aequalis, Poa annua, and Polypogon fugax) at the dosage of 150 g a.i./ha through postemergence application in a greenhouse. This work identified a novel lead compound (10bh) that showed good activity in vitro and excellent herbicidal activity in vivo and had promising prospects as a new PPO-inhibiting herbicide lead.

Anilino-1,4-naphthoquinones as potent mushroom tyrosinase inhibitors: in vitro and in silico studies.

Tyrosinase, a pivotal enzyme in melanin synthesis, is a primary target for the development of depigmenting agents. In this work, in vitro and in silico techniques were employed to identify novel tyrosinase inhibitors from a set of 12 anilino-1,4-naphthoquinone derivatives. Results from the mushroom tyrosinase activity assay indicated that, among the 12 derivatives, three compounds (1, 5, and 10) demonstrated the most significant inhibitory activity against mushroom tyrosinase, surpassing the effectiveness of the kojic acid. Molecular docking revealed that all studied derivatives interacted with copper ions and amino acid residues at the enzyme active site. Molecular dynamics simulations provided insights into the stability of enzyme-inhibitor complexes, in which compounds 1, 5, and particularly 10 displayed greater stability, atomic contacts, and structural compactness than kojic acid. Drug likeness prediction further strengthens the potential of anilino-1,4-naphthoquinones as promising candidates for the development of novel tyrosinase inhibitors for the treatment of hyperpigmentation disorders.

New synergistic benzoquinone scaffolds as inhibitors of mycobacterial cytochrome bc1 complex to treat multi-drug resistant tuberculosis.

Through a comprehensive molecular docking study, a unique series of naphthoquinones clubbed azetidinone scaffolds was arrived with promising binding affinity to Mycobacterial Cytbc1 complex, a drug target chosen to kill multi-drug resistant Mycobacterium tuberculosis (MDR-Mtb). Five compounds from series-2, 2a, 2c, 2g, 2h, and 2j, showcased significant in vitro anti-tubercular activities against Mtb H37Rv and MDR clinical isolates. Further, synergistic studies of these compounds in combination with INH and RIF revealed a potent bactericidal effect of compound 2a at concentration of 0.39 µg/mL, and remaining (2c, 2g, 2h, and 2j) at 0.78 µg/mL. Exploration into the mechanism study through chemo-stress assay and proteome profiling uncovered the down-regulation of key proteins of electron-transport chain and Cytbc1 inhibition pathway. Metabolomics corroborated these proteome findings, and heightened further understanding of the underlying mechanism. Notably, in vitro and in vivo animal toxicity studies demonstrated minimal toxicity, thus underscoring the potential of these compounds as promising anti-TB agents in combination with RIF and INH. These active compounds adhered to Lipinski's Rule of Five, indicating the suitability of these compounds for drug development. Particular significance of molecules NQ02, 2a, and 2h, which have been patented (Published 202141033473).

Inhibitory interactions of the 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one scaffold with Bunyavirales cap-snatching endonucleases expose relevant drug design features.

The World Health Organization (WHO) identifies several bunyaviruses as significant threats to global public health security. Developing effective therapies against these viruses is crucial to combat future outbreaks and mitigate their impact on patient outcomes. Here, we report the synthesis of some isoindol-1-one derivatives and explore their inhibitory properties over an indispensable metal-dependent cap-snatching endonuclease (Cap-ENDO) shared among evolutionary divergent bunyaviruses. The compounds suppressed RNA hydrolysis by Cap-ENDOs, with IC50 values predominantly in the lower µM range. Molecular docking studies revealed the interactions with metal ions to be essential for the 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one scaffold activity. Calorimetric analysis uncovered Mn2+ ions to have the highest affinity for sites within the targets, irrespective of aminoacidic variations influencing metal cofactor preferences. Interestingly, spectrophotometric findings unveiled sole dinuclear species formation between the scaffold and Mn2+. Moreover, the complexation of two Mn2+ ions within the viral enzymes appears to be favourable, as indicated by the binding of compound 11 to TOSV Cap-ENDO (Kd = 28 ± 3 µM). Additionally, the tendency of compound 11 to stabilize His+ more than His- Cap-ENDOs suggests exploitable differences in their catalytic pockets relevant to improving specificity. Collectively, our results underscore the isoindolinone scaffold's potential as a strategic starting point for the design of pan-antibunyavirus drugs.

3D-QSAR-Directed Synthesis of Halogenated Coumarin-3-Hydrazide Derivatives: Unveiling Their Potential as SDHI Antifungal Agents.

The pursuit of new succinate dehydrogenase (SDH) inhibitors is a leading edge in fungicide research and development. The use of 3D quantitative structure-activity relationship (3D-QSAR) models significantly enhances the development of compounds with potent antifungal properties. In this study, we leveraged the natural product coumarin as a molecular scaffold to synthesize 74 novel 3-coumarin hydrazide derivatives. Notably, compounds 4ap (0.28 µg/mL), 6ae (0.32 µg/mL), and 6ah (0.48 µg/mL) exhibited exceptional in vitro effectiveness against Rhizoctonia solani, outperforming the commonly used fungicide boscalid (0.52 µg/mL). Furthermore, compounds 4ak (0.88 µg/mL), 6ae (0.61 µg/mL), 6ah (0.65 µg/mL), and 6ak (1.11 µg/mL) showed significant activity against Colletotrichum orbiculare, surpassing both the SDHI fungicide boscalid (43.45 µg/mL) and the broad-spectrum fungicide carbendazim (2.15 µg/mL). Molecular docking studies and SDH enzyme assays indicate that compound 4ah may serve as a promising SDHI fungicide. Our ongoing research aims to refine this 3D-QSAR model further, enhance molecular design, and conduct additional bioactivity assays.

Design, Synthesis, and Pharmacological Evaluation of Spiro[carbazole-3,3'-pyrrolidine] Derivatives as cGAS Inhibitors for Treatment of Acute Lung Injury.

Overactivation of cyclic GMP-AMP synthase (cGAS) is implicated in the occurrence of many inflammatory and autoimmune diseases, and inhibition of cGAS with a specific inhibitor has been proposed as a potential therapeutic strategy. However, only a few low-potency cGAS inhibitors have been reported, and few are suitable for clinical investigation. As a continuation of our structural optimization on the reported cGAS inhibitor 6 (G140), we developed a series of spiro[carbazole-3,3'-pyrrolidine] derivatives bearing a unique 2-azaspiro[4.5]decane structural motif, among which compound 30d-S was identified with high cellular effects against cGAS. This compound showed improved plasma exposure, lower clearance, and an oral bioavailability of 35% in rats. Moreover, in the LPS-induced acute lung injury (ALI) mice model, oral administration of compound 30d-S at 30 mg/kg markedly reduced lung inflammation and alleviated histopathological changes. These results confirm that 30d-S is a new efficacious cGAS inhibitor and is worthy of further investigation.

Inhibition of kynurenine production by N,O-substituted hydroxylamine derivatives.

The inhibition of kynurenine production is considered a promising target for cancer immunotherapy. In this study, an amino acid derivative, compound 1 was discovered using a cell-based assay with our screening library. Compound 1 suppressed kynurenine production without inhibiting indoleamine 2,3-dioxygenase 1 (IDO1) activity. The activity of 1 was derived from the inhibition of IDO1 by a metabolite of 1, O-benzylhydroxylamine (OBHA, 2a). A series of N-substituted 2a derivatives that exhibit potent activity in cell-based assays may represent effective prodrugs. Therefore, we synthesized and evaluated novel N,O-substituted hydroxylamine derivatives. The structure-activity relationships revealed that N,O-substituted hydroxylamine 2c inhibits kynurenine production in a cell-based assay. We conducted an in vivo experiment with 2c, although the effectiveness of O-substituted hydroxylamine derivatives in vivo has not been previously reported. The results indicate that N,O-substituted hydroxylamine derivatives are promising IDO1 inhibitors.

Replacement of sulfonamide by sulfoximine within a helicase-primase inhibitor with restricted flexibility.

Helicase-primase is an interesting target for the therapy of herpes simplex virus (HSV) infections. Since amenamevir is already approved for varicella-zoster virus (VZV) and HSV in Japan and pritelivir has received breakthrough therapy status for the treatment of acyclovir-resistant HSV infections in immunocompromised patients, the target has sparked interest in me-too approaches. Here, we describe the attempt to improve nervous tissue penetration in Phaeno Therapeutics drug candidate HN0037 to target the latent reservoir of HSV by installing less polar moieties, mainly a difluorophenyl instead of a pyridyl group, and replacing the primary sulfonamide with a methyl sulfoximine moiety. However, all obtained stereoisomers exhibited a weaker inhibitory activity on HSV-1 and HSV-2.

Reverse N-Substituted Hydroxamic Acid Derivatives of Fosmidomycin Target a Previously Unknown Subpocket of 1-Deoxy-d-xylulose 5-Phosphate Reductoisomerase (DXR).

Reverse analogs of the phosphonohydroxamic acid antibiotic fosmidomycin are potent inhibitors of the nonmevalonate isoprenoid biosynthesis enzyme 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR, IspC) of Plasmodium falciparum. Some novel analogs with large phenylalkyl substituents at the hydroxamic acid nitrogen exhibit nanomolar PfDXR inhibition and potent in vitro growth inhibition of P. falciparum parasites coupled with good parasite selectivity. X-ray crystallographic studies demonstrated that the N-phenylpropyl substituent of the newly developed lead compound 13e is accommodated in a subpocket within the DXR catalytic domain but does not reach the NADPH binding pocket of the N-terminal domain. As shown for reverse carba and thia analogs, PfDXR selectively binds the S-enantiomer of the new lead compound. In addition, some representatives of the novel inhibitor subclass are nanomolar Escherichia coli DXR inhibitors, whereas the inhibition of Mycobacterium tuberculosis DXR is considerably weaker.

Discovery of TNG908: A Selective, Brain Penetrant, MTA-Cooperative PRMT5 Inhibitor That Is Synthetically Lethal with MTAP-Deleted Cancers.

It has been shown that PRMT5 inhibition by small molecules can selectively kill cancer cells with homozygous deletion of the MTAP gene if the inhibitors can leverage the consequence of MTAP deletion, namely, accumulation of the MTAP substrate MTA. Herein, we describe the discovery of TNG908, a potent inhibitor that binds the PRMT5·MTA complex, leading to 15-fold-selective killing of MTAP-deleted (MTAP-null) cells compared to MTAPintact (MTAP WT) cells. TNG908 shows selective antitumor activity when dosed orally in mouse xenograft models, and its physicochemical properties are amenable for crossing the blood-brain barrier (BBB), supporting clinical study for the treatment of both CNS and non-CNS tumors with MTAP loss.