Key structural requirements of benzamide derivatives for histone deacetylase inhibition: design, synthesis and biological evaluation.

Background: Histone deacetylase inhibitors (HDACIs) are important as anticancer agents. Objective: This study aimed to investigate some key structural features of HDACIs via the design, synthesis and biological evaluation of novel benzamide-based derivatives. Methods: Novel structures, designed using a molecular modification approach, were synthesized and biologically evaluated. Results: The results indicated that a subset of molecules with CH3/NH2 at R2 position possess selective antiproliferative activity. However, only those with an NH2 group showed HDACI activity. Importantly, the shorter the molecule length, the stronger HDACI. Among all, 7j was the most potent HDAC1-3 inhibitor and antiproliferative compound. Conclusion: The results of the present investigation could provide valuable structural knowledge applicable for the development of the HDACIs and benzamide-based antiproliferative agents in the future.

[Box: see text].

Current trends in development of HDAC-based chemotherapeutics.

BACKGROUND: Histone deacetylases (HDACs) are one of the essential epigenetic targets in cancer treatment. These enzymes play key roles in post-translation modification (PTM) and gene expression, and consequently, their inhibitors are about to find their place in pharmacotherapy. Most of the currently approved HDAC inhibitors (HDACIs) are wide-spectrum with poor clinical outcomes and numerous side effects. Therefore, new generations of HDAC-based chemotherapeutics with better clinical outcomes are emerging, e.g., isoform-selective inhibitors, multitargeted HDACIs, as well as HDAC degraders. AIM: The review intended to introduce drug design approaches which were used for designing novel agents which can be beneficial in the process of finding new and more effective HDACI-based therapeutics. METHODS: PubMed and other databases were searched for literature regarding the structure-function of HDAC isoforms, and strategies used to design HDAC inhibitors. Also, all clinical trials available from the ClinicalTrials site for years 2021-2022 were investigated. KEY FINDINGS: It is expected that the future of drug discovery projects in HDAC field will concentrate mostly on issues such as isoform-selectivity, multitargeted HDAC inhibitors and HDAC degraders. Deeper knowledge of the 3D structure of HDACs complexed with inhibitors and extensive delineation of biological roles of HDACs are needed for efficient investigations leading to the discovery of novel potent inhibitors. SIGNIFICANCE: Histone deacetylases (HDACs) are one of the important epigenetic targets in cancer treatment drug discovery. Comprehending the structure of HDAC isoforms along with applied drug design strategies can inspire new ideas.

Development of New Inhibitors of HDAC1-3 Enzymes Aided by In Silico Design Strategies.

Histone deacetylases (HDACs) are overexpressed in cancer, and their inhibition shows promising results in cancer therapy. In particular, selective class I HDAC inhibitors such as entinostat are proposed to be more beneficial in breast cancer treatment. Computational drug design is an inevitable part of today's drug discovery projects because of its unequivocal role in saving time and cost. Using three HDAC inhibitors trichostatin, vorinostat, and entinostat as template structures and a diverse fragment library, all synthetically accessible compounds thereof (∼3200) were generated virtually and filtered based on similarity against the templates and PAINS removal. The 298 selected structures were docked into the active site of HDAC I and ranked using a calculated binding affinity. Top-ranking structures were inspected manually, and, considering the ease of synthesis and drug-likeness, two new structures (3a and 3b) were proposed for synthesis and biological evaluation. The synthesized compounds were purified to a degree of more than 95% and structurally verified using various methods. The designed compounds 3a and 3b showed 65-80 and 5% inhibition on HDAC 1, 2, and 3 isoforms at a concentration of 10 µM, respectively. The novel compound 3a may be used as a lead structure for designing new HDAC inhibitors.

Aldehyde oxidase at the crossroad of metabolism and preclinical screening.

Human AOX1 is a member of the mammalian aldehyde oxidase (AOX) family of enzymes and it is an emerging cytosolic enzyme involved in phase I drug-metabolism, bio-transforming a number of therapeutic agents and xenobiotics. The current trend in drug-development is to design molecules which are not recognized and inactivated by CYP450 monooxygenases, the main drug-metabolizing system, to generate novel therapeutic agents characterized by optimal pharmacokinetic and pharmacodynamic properties. Unfortunately, this has resulted in a substantial enrichment in molecules which are recognized and metabolized by AOXs. The observation has raised interest in the generation of tools capable of predicting AOX-dependent drug-metabolism of novel molecules during the early phases of drug development. Such tools are likely to reduce the number of failures occurring at the clinical and late phase of the drug development process. The current review describes different in silico, in vitro and in vivo methods for the prediction of AOX metabolizing ability and focuses on the existing drawbacks and challenges associated with these approaches.