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We introduce the Center for Research and Advancement in Fragments and Molecular Targets (CRAFT), a pioneering research center established in 2021 through a collaboration between the University of São Paulo (USP) and the Federal University of Goiás (UFG). CRAFT integrates fragment-based drug discovery (FBDD), artificial intelligence (AI), and structural biology to develop novel therapeutic strategies. We have created fragment and target libraries and utilize AI models to streamline the drug discovery process. We invite the global scientific community to collaborate with us in addressing neglected diseases, with the goal of enhancing research capabilities and fostering scientific innovation across Latin America., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Genome stability is governed by chromatin structural dynamics, which modify DNA accessibility under the influence of intra- and inter-nucleosomal contacts, histone post-translational modifications (PTMs) and variations, besides the activity of ATP-dependent chromatin remodelers. These are the main ways by which chromatin dynamics are regulated and connected to nuclear processes, which when dysregulated can frequently be associated with most malignancies. Recently, functional crosstalk between histone modifications and chromatin remodeling has emerged as a critical regulatory method of transcriptional regulation during cell destiny choice. Therefore, improving therapeutic outcomes for patients by focusing on epigenetic targets dysregulated in malignancies should help prevent cancer cells from developing resistance to anticancer treatments. For this reason, SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) has gained a lot of attention recently as a cancer target. SETDB1 is a histone lysine methyltransferase that plays an important role in marking euchromatic and heterochromatic regions. Hence, it promotes the silencing of tumor suppressor genes and contributes to carcinogenesis. Some studies revealed that SETDB1 was overexpressed in various human cancer types, which enhanced tumor growth and metastasis. Thus, SETDB1 appears to be an attractive epigenetic target for new cancer treatments. In this review, we have discussed the effects of its overexpression on the progression of tumors and the development of inhibitor drugs that specifically target this enzyme., Competing Interests: There is no conflict of interest to declare., (This journal is © The Royal Society of Chemistry.)

The urgent need for effective treatments against emerging viral diseases, driven by drug-resistant strains and new viral variants, remains critical. We focus on inhibiting the human dihydroorotate dehydrogenase ( Hs DHODH), one of the main enzymes responsible for pyrimidine nucleotide synthesis. This strategy could impede viral replication without provoking resistance. We evaluated naphthoquinone fragments, discovering potent Hs DHODH inhibition with IC 50 ranging from 48 to 684 nM, and promising in vitro anti-SARS-CoV-2 activity with EC 50 ranging from 1.2 to 2.3 μM. These compounds exhibited low toxicity, indicating potential for further development. Additionally, we employed computational tools such as molecular docking and quantitative structure-activity relationship (QSAR) models to analyze protein-ligand interactions, revealing that these naphthoquinones exhibit a protein binding pattern similar to brequinar, a potent Hs DHODH inhibitor. These findings represent a significant step forward in the search for effective antiviral treatments and have great potential to impact the development of new broad-spectrum antiviral drugs., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Heterocycles are a cornerstone of fragment-based drug discovery (FBDD) due to their prevalence in biologically active compounds. However, novel heterocyclic fragments are only valuable if they can be suitably elaborated to compliment a chosen target protein. Here we describe the synthesis of 5-halo-1 H -pyrazolo[3,4- c ]pyridine scaffolds and demonstrate how these compounds can be selectively elaborated along multiple growth-vectors. Specifically, N-1 and N-2 are accessed through protection-group and N -alkylation reactions; C-3 through tandem borylation and Suzuki-Miyaura cross-coupling reactions; C-5 through Pd-catalysed Buchwald-Hartwig amination; and C-7 through selective metalation with TMPMgCl . LiCl followed by reaction with electrophiles or transmetalation to ZnCl 2 and Negishi cross-coupling. Linking multiple functionalisation strategies emulates a hit-to-lead pathway and demonstrates the utility of pyrazolo[3,4- c ]pyridines to FBDD., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Trypanosoma cruzi , the etiological agent of Chagas disease, relies on finely coordinated epigenetic regulation during the transition between hosts. Herein we targeted the silent information regulator 2 (Sir2) enzyme, a NAD + -dependent class III histone deacetylase, to interfere with the parasites' cell cycle. A combination of molecular modelling with on-target experimental validation was used to discover new inhibitors from commercially available compound libraries. We selected six inhibitors from the virtual screening, which were validated on the recombinant Sir2 enzyme. The most potent inhibitor (CDMS-01, IC 50 = 40 μM) was chosen as a potential lead compound.

Background: Plasmodium falciparum has shown multidrug resistance, leading to the necessity for the development of new drugs with novel targets, such as the synthesis of isoprenic precursors, which are excellent targets because the pathway is different in several steps when compared with the human host. Naphthoquinone derivatives have been described as potentially promising for the development of anti-malarial leader molecules. In view of that, the focus in this work is twofold: first, evaluate the in vitro naphthoquinone antiplasmodial activity and cytotoxicity; secondly, investigate one possible action mechanism of two derivatives of hydroxy-naphthoquinones., Results: The two hydroxy-naphthoquinones derivatives have been tested against P. falciparum in vitro, using strains of parasites chloroquine-sensitive (3D7) and chloroquine-resistant (Dd2), causing 50% inhibition of parasite growth with concentrations that varied from 7 to 44.5 μM. The cell viability in vitro against RAW Cell Line displayed IC 50  = 483.5 and 714.9 μM, whereas, in primary culture tests using murine macrophages, IC 50 were 315.8 and 532.6 μM for the two selected compounds, causing no haemolysis at the doses tested. The in vivo acute toxicity assays exhibited a significant safety margin indicated by a lack of systemic and behavioural toxicity up to 300 mg/kg. It is suggested that this drug seems to inhibit the biosynthesis of isoprenic compounds, particularly the menaquinone and tocopherol., Conclusions: These derivatives have a high potential for the development of new anti-malarial drugs since they showed low toxicity associated to a satisfactory antiplasmodial activity and possible inhibition of a metabolic pathway distinct from the pathways found in the mammalian host.

A concise strategy for the synthesis of 2,3-substituted furo[2,3-b]pyridines is described. Mild, metal-free conditions were successfully applied to produce a range of 2-(alkyl or aryl)-3-ethylcarboxylate-furo[2,3-b]pyridines in yields of 50-91%. Then, the chemical reactivity of this heterocyclic framework was explored to develop straightforward methods for its functionalization. The pyridine moiety reactivity was successfully explored by C-H amination and borylation reactions, although C-H fluorination and radical C-H arylation processes were not as efficient. In addition, while the furopyridine core proved stable under basic conditions, the ring-opening reaction of the furan moiety with hydrazine generated a valuable new pyridine-dihydropyrazolone scaffold.

The 1,4-naphthoquinones, important members of the family of quinones are used as both crude extracts and as compound manipulated by the pharmaceutical industry. They have gained great emphasis by presenting different pharmacological properties as antibacterial, antiviral, antiprotozoal and anthelmintic, and has antitumor activity. Our aim was to evaluate the cytotoxicity, hemolytic activity and in vivo acute toxicity of three derivatives of 2-hydroxy-1,4-naphthoquinones. The cell viability in vitro against RAW Cell Line displayed IC 50 ranging of 483.5-2044.8 μM, whereas in primary culture tests using murine macrophages, IC 50 were 315.8-1408.0 μM for naphthoquinones derivatives 4a and 4c respectively, besides no hemolysis was observed at the dose tested. The in vivo acute toxicity assays exhibited a significant safety margin indicated by a lack of systemic and behavioral toxicity up to 300 mg/kg, and at a dose of 1000 mg/kg the derivatives not triggering signs of toxicity although the compound 4a have promoted hepatic steatosis and hyperemia in kidney tissue. Thereby, these modifications decrease the toxicity of the tested derivatives naphthoquinones, providing a high potential for the development of news drugs.