Benzothiazole structures are widely present in many drugs and natural product molecules. A renewal of interest in 2-cyanobenzothiazole derivatives is mainly prompted by their noteworthy utility for bioimaging. Their reactivity stems from the presence of an electrophilic site, making them highly versatile and enabling a diversity of transformations. The increasing prominence of bioorthogonal chemistry has further elevated the importance of 2-cyanobenzothiazole, establishing it as a key building block in organic synthesis. In the present review, we highlight the huge interest in the synthesis of 2-cyanobenzothiazole as a stepping stone in the development of the biomedical research. A general overview of common methods as well as research progress in the synthetic approaches will be discussed.

Unbiased kinome-wide CRISPR screening identified DYRK1A as a potential therapeutic target in KMT2A-rearranged (KMT2A-R) B-acute lymphoblastic leukemia (ALL). Mechanistically, we demonstrate that DYRK1A is regulated by the KMT2A fusion protein and affects cell proliferation by regulating MYC expression and ERK phosphorylation. We further observed that pharmacologic DYRK1A inhibition markedly reduced human KMT2A-R ALL cell proliferation in vitro and potently decreased leukemia proliferation in vivo in drug-treated patient-derived xenograft mouse models. DYRK1A inhibition induced expression of the proapoptotic factor BIM and reduced the expression of BCL-XL, consequently sensitizing KMT2A-R ALL cells to BCL2 inhibition. Dual inhibition of DYRK1A and BCL2 synergistically decreased KMT2A-R ALL cell survival in vitro and reduced leukemic burden in mice. Taken together, our data establishes DYRK1A as a novel therapeutic target in KMT2A-R ALL and credential dual inhibition of DYRK1A and BCL2 as an effective translational therapeutic strategy for this high-risk ALL subtype.

Background/Objectives: Biofilm-associated infections pose a major clinical challenge since bacteria within biofilms exhibit highly antibiotic tolerance. Pseudomonas aeruginosa forms persistent biofilms that cause chronic infections in vulnerable patients, including those with cystic fibrosis, burns, or medical implants. Such biofilm-associated chronic infections require prolonged treatments that promote antimicrobial resistance. To address this, recent strategies focus on enhancing biofilm dispersion. Methods: Thirty-six N-arylimino-1,2,3-dithiazoles were screened for their biofilm dispersal activity using a crystal violet assay. Their cytotoxicity was assessed on A549 and HaCat eukaryotic cells. Moreover, their influence on bacterial growth and virulence was investigated. Lastly, fluorescence anisotropy was used to measure membrane fluidity to obtain the first insights on the mechanism of action of these chemicals. Results: Our results showed that quinazoline-derivatives of imino-1,2,3-dithiazoles display biofilm dispersion activity. These compounds do not increase virulence through pyocyanin production, do not modify the growth kinetics of P. aeruginosa, and do not show cytotoxicity towards eucaryotic cells. Conclusions: These findings highlight the potential use of N-arylimino-1,2,3-dithiazole-derived compounds as safe and effective dispersal agents of P. aeruginosa biofilms.

Background: B-acute lymphoblastic leukemia (ALL) is the most common childhood cancer and is driven primarily by oncogenic chromosomal rearrangements and gene fusions. While overall survival rates are nearly 90% in children and about 40% in adults with good- and intermediate-risk ALL subtypes, clinical outcomes of patients with high-risk ALL subtypes, including KMT2A-rearranged (KMT2A-R), are significantly lower, posing an urgent need to develop novel therapeutic strategies for these patient populations. Results: To identify targetable kinases and potential precision medicine approaches in KMT2A-R ALL, we conducted domain-specific kinome-wide CRISPR screens and found the serine/threonine kinase DYRK1A essential for KMT2A-R ALL proliferation. The Cancer Dependency MAP suggests DYRK1A is non-essential for normal tissues, indicating a potential therapeutic window. RT-PCR and Western blot analyses showed increased DYRK1A expression levels in KMT2A-R ALL cell lines and patient-derived xenograft (PDX) samples compared to other leukemia subtypes, suggesting direct regulation by the KMT2A-fusion oncogene. Meta-analysis of ChIP-seq data confirmed direct binding of the KMT2A-fusion protein to the DYRK1A promoter. Inhibition of menin, a tumor suppressor protein that forms a complex with the KMT2A-fusion protein, reduced DYRK1A expression at RNA and protein levels and prevented the binding of the KMT2A-fusion protein to the DYRK1A promoter, validating the direct regulation of DYRK1A by the KMT2A-fusion oncogene. To test the consequence of direct pharmacologic inhibition of DYRK1A using EHT1610 and harmine, we treated multiple KMT2A-R ALL cell lines and PDX models, validating potent inhibition of leukemia cell growth without inducing apoptosis. Furthermore, we detected potent upregulation of MYC and hyperphosphorylation of ERK. Premature ERK signaling activation in developing B cells is known to induce cell cycle arrest as a protective mechanism to prevent the development of autoimmune diseases. We hypothesized that DYRK1A inhibitor-induced ERK hyperactivation leads to cell cycle arrest in KMT2A-R ALL via a similar mechanism. Supporting our hypothesis, combining DYRK1A inhibitors with the MEK inhibitor trametinib rescued KMT2A-R ALL cell proliferation, validating that ERK hyperactivation is the main driver of DYRK1A inhibitor-mediated cell cycle arrest. Interestingly, although DYRK1A inhibition mainly affected cell proliferation, we detected a potent increase in the pro-apoptotic molecule BIM. BIM is inactivated by the anti-apoptotic molecule BCL2, which was also slightly increased after DYRK1A inhibition, indicating that DYRK1A inhibitors could also sensitize KMT2A-R ALL cells to BCL2 inhibition (e.g., venetoclax). In support of our hypothesis, combined treatment with DYRK1A inhibitors and venetoclax synergistically killed KMT2A-R ALL cells in vitro. Given the poor pharmacodynamics and severe toxicity of EHT1610 and harmine, we synthesized a new DYRK1A inhibitor, GNF2133, and tested its activity in vitro against KMT2A-R ALL cell lines and in vivo +/- venetoclax in KMT2A-R ALL PDX models. Importantly, both GNF2133 and venetoclax were well tolerated in xenograft mice, and combination inhibitor therapy resulted in superior inhibition of in vivo leukemia proliferation and long-term animal survival. Conclusion: Our results identify DYRK1A as a critical regulator of ERK signaling in KMT2A-R ALL. DYRK1A inhibition leads to BIM accumulation, sensitizing cells to BCL2 inhibition by venetoclax in vitro and in vivo and resulting in therapeutic benefit in preclinical PDX models that is highly translatable to the clinic.

Based on a multitarget approach implementing rivastigmine-INDY hybrids 1, we identified a set of pseudo-irreversible carbamate-type inhibitors of eqBuChE that, after carbamate transfer at the active site serine residue, released the corresponding INDY analogues 2 endowed with hDYRK1A/hCLK1 kinases inhibitory properties. A SAR study and molecular docking investigation of both series of compounds 1 and 2 revealed that appropriate structural modifications at the carbamate moiety and at the N-appendage of the benzothiazole core led to potent and selective eqBuChE inhibitors with IC50 up to 27 nM and potent hDYRK1A and hCLK1 inhibitors with IC50 up to 106 nM and 17 nM respectively. Pleasingly, identification of the matched pair of compounds 1b/2b with a good balance between inhibition of eqBuChE and hDYRK1A/hCLK1 kinases (IC50 = 68 nM and IC50 = 529/54 nM, respectively) further validated our multitarget approach based on a sequential mechanism of action. In addition, target compound 1b exhibited a suitable ADMET profile, including good brain permeability and high stability in PBS, encouraging further biological investigation as a drug candidate. Promising multitargets ligands in Alzheimer's disease: sequential BuChE and DYRK1A/CLK1 kinases inhibition.

The synthesis of thiazole-fused derivatives of tricyclic quinazolinones hitherto undescribed was successfully achieved by re-placing anthranilic acid or its derivatives by isomeric polyfunctionalized benzothiazole analogues of anthranilic methyl esters. Some of the new heterocyclic systems are inspired by natural alkaloids such as mackinazolinone, deoxyvasicinone, and isaindigotone, showing interesting biological properties. The microwave-assisted method developed is a variant of the Niementowski reaction and was also applied to the synthesis of ring-extended rutaecarpine derivatives

Sulfur transfer reagents play an important role in organic synthesis, and sulfur chlorides, especially disulfur dichloride, are exceptional examples. Professor Charles W. Rees proposed novel strategies for preparing sulfur -nitrogen heterocycles from readily available organic substrates using disulfur dichloride. Together with his coworkers, he developed cascade transformations for synthesizing a wide range of heterocyclic systems, including 1,2-dithioles, 1,2,3,4,5-pentathiepins, 1,2,3-dithiazoles, 1,2,5-thiadiazoles, 1,4-thiazines, and 1,2,3,4,5,6,7-heptathiocanes. This review highlights Professor Rees's contributions to the chemistry of disulfur dichloride.

Background/Objectives: In connection with previous work on V-shaped polycyclic thiazolo[5,4-f]quinazolin-9-one and [5,4-f]quinazoline derivatives that can modulate the activity of various kinases, the synthesis of straight thiazole-fused [4,5-g] or [5,4-g]quinazolin-8-ones and quinazoline derivatives hitherto undescribed was envisioned. Methods: An innovative protocol allowed to obtain the target structures. The synthesis of inverted thiazolo[4,5-h] and [5,4-h]quinazolin-8-one derivatives was also explored with the aim of comparing biological results. The compounds obtained were tested against a representative panel of eight mammalian protein kinases of human origin: CDK9/CyclinT, Haspin, Pim-1, GSK-3β, CK-1ε, JAK3, CLK1 and DYRK1A. Results and Conclusions: The results obtained show that the novel linear thiazoloquinazolines are not kinase inhibitors. The cytotoxicity of these newly synthesized compounds was assessed against seven representative tumor cell lines (human cancers: Huh7-D12, Caco-2, HCT-116, MCF-7, MDA-MB-231, MDA-MB-468 and PC-3). The majority of these novel molecules proved capable of inhibiting the growth of the tested cells. The 7-Benzyl-8-oxo-7,8-dihydrothiazolo[5,4-g]quinazolinones 5b and 6b are the most potent, with IC50 values in the micromolar range. None of these compounds showed toxicity against normal cells. A larger program of investigations will be launched to investigate the real potential interest of such compounds in anticancer applications.

The DYRK (Dual-specificity tyrosine phosphorylation-regulated kinase) family of protein kinases is involved in the pathogenesis of several neurodegenerative diseases. Among them, the DYRK1A protein kinase is thought to be implicated in Alzheimer's disease (AD) and Down syndrome, and as such, has emerged as an appealing therapeutic target. DYRKs are a subset of the CMGC (CDK, MAPKK, GSK3 and CLK) group of kinases. Within this group of kinases, the CDC2-like kinases (CLKs), such as CLK1, are closely related to DYRKs and have also sparked great interest as potential therapeutic targets for AD. Based on inhibitors previously described in the literature (namely TG003 and INDY), we report in this work a new class of dihydroquinolines exhibiting inhibitory activities in the nanomolar range on hDYRK1A and hCLK1. Moreover, there is overwhelming evidence that oxidative stress plays an important role in AD. Pleasingly, the most potent dual kinase inhibitor 1p exhibited antioxidant and radical scavenging properties. Finally, drug-likeness and molecular docking studies of this new class of DYRK1A/CLK1 inhibitors are also discussed in this article.

The synthesis of trifunctional isomeric benzothiazoles derived from nitroanthranilic acids and their corresponding anthranilonitrile analogues is studied. Compared to previous work, the reaction sequence affords convenient access to hitherto undescribed 2-cyanobenzothiazoles. For further synthetic applications of these poly-functional compounds, a hydrolysis-decarboxylation sequence is per -formed in an acidic medium (HCl or HBr), leading to an enlarged array of relevant building blocks.

A practical and sustainable photocatalyst-free protocol for photoinduced synthesis of perfluoroalkylated quinazolin-4(3H)-ones is described starting from quinazolin-4(3H)-ones. A wide range of substituted or fused-quinazolinones is found to be compatible, providing the corresponding mono- and bis-perfluoroalkylated compounds in moderate yields. This visible-light-mediated C–H perfluoroalkylation allows an environmentally friendly and straightforward access to an array of unprecedented functionalized quinazolinone scaffolds, presenting attractive features for drug discovery. Control experiments demonstrated that a radical mechanism is involved in the reaction mechanism.

In order to prepare an array of beta-cyanoenamine derivatives as potential precursors of heterocyclic systems with pharmaceutical interest, the synthesis of fifteen polyfunctionalized 4H-chromenes was realized via a microwave-assisted and catalyst-free three-component reaction. Microwave-heated reactions were monitored by Raman spectroscopy, enabling a fast and efficient setting of the process parameters. This study confirms that this monitoring tool may have some limitations linked to homogeneity of reaction medium. This work also investigates the use of some bio-sourced and sustainable solvents currently studied in many works. Ethanol remains the most suitable for this synthesis.

Objective. - Our aim was to define a repository of competences in Medicinal Chemistry, to be developed during Pharmacy studies and expected in professional practices, while highlighting the fundamental character of the subject and its interdisciplinary links within the Pharmaceutical Sciences. Methods. - A first version, based on both our professional and educational experience, consolidated by a review of educational articles and good practice guidelines, was obtained by following a competency-based approach. It was then completed by Medicinal Chemistry teachers in various French Pharmacy Faculties to obtain a comprehensive data set. The final version was reviewed in the light of relevant comments from 15 experts from related disciplines. Results. - A comprehensive competency framework with extensive practical applications was developed. Conclusions. - This pilot study provides a teaching repository for medicinal chemistry for use by teachers of medicinal sciences. It highlights the fundamental role of the discipline within Pharmacy studies and provides links with professional practices. This repository will be useful to various teaching teams in a context of integrated disciplines and could be replicated in related disciplines. (c) 2021 Acad ' emie Nationale de Pharmacie. Published by Elsevier Masson SAS. All rights reserved.

The objective of this review is to list the structures composed of a pyridopyrimidine moiety which have shown a therapeutic interest or have already been approved for use as therapeutics. We consider all the synthetic protocols to prepare these pyridopyrimidine derivatives. The review is organized into four sections, successively pyrido[2,3-d]pyrimidines, pyrido[3,4-d]pyrimidines, pyrido[4,3-d]pyrimidines and pyrido[3,2-d]pyrimidines. For each compound we present the biological activity and the synthetic route reported. To produce this manuscript, the bibliographic research was done using Reaxys and Scifinder for each kind of pyridopyrimidine.

In this study we show that glycosylation is relevant for immune recognition of therapeutic antibodies, and that defined glycan structures can modulate immunogenicity. Concerns regarding immunogenicity arise from the high heterogeneity in glycosylation that is difficult to control and can deviate from human glycosylation if produced in non-human cell lines. While non-human glycosylation is thought to cause hypersensitivity reactions and immunogenicity, less is known about effects of Fc-associated glycan structures on immune cell responses. We postulated that glycosylation influences antigen recognition and subsequently humoral responses to therapeutic antibodies by modulating 1) recognition and uptake by dendritic cells (DCs), and 2) antigen routing, processing and presentation. Here, we compared different glycosylation variants of the antibody rituximab (RTX) in in vitro assays using human DCs and T cells as well as in in vivo studies. We found that human DCs bind and internalize unmodified RTX stronger compared to its aglycosylated form suggesting that glycosylation mediates uptake after recognition by glycan-specific receptors. Furthermore, we show that DC-uptake of RTX increases or decreases if glycosylation is selectively modified to recognize activating (by mannosylation) or inhibitory lectin receptors (by sialylation). Moreover, glycosylation seems to influence antigen presentation by DCs because specific glycovariants tend to induce either stronger or weaker T cell activation. Finally, we demonstrate that antibody glycosylation impacts anti-drug antibody (ADA) responses to RTX in vivo. Hence, defined glycan structures can modulate immune recognition and alter ADA responses. Glyco-engineering may help to decrease clinical immunogenicity and ADA-associated adverse events such as hypersensitivity reactions.

We report herein on a catalytic system involving palladium and copper to achieve the cyclization of N-arylcyanothioformamides and the synthesis of 2-cyanobenzothiazoles. The C-H functionalization/intramolecular C-S bond formation reaction was achieved in the presence of air, using 2.0 equiv of an inorganic additive (KI). In many cases, the reaction led to a sole product regioselectively obtained in good yields, allowing the synthesis of a wide range of substituted 2-cyanobenzothiazole derivatives, providing valuable building blocks for the design of more complex heterocyclic or molecular labeling systems.