Current Drug Targets - Volume 24, Issue 9, 2023

Background: Tropolone and thailandepsin B are naturally occurring substances that are primarily isolated from fungi and plants, although they can also be found in certain bacteria. Tropolones belong to an important class of aromatic compounds with a seven-membered nonbenzenoid ring structure. Thailandepsins are a group of natural products that were initially discovered in the culture broth of the Gram-negative bacterium Burkholderia thailandensis. Tropolonebased structures have been identified in over 200 natural compounds, ranging from simple tropolone derivatives to complex multicyclic systems like pycnidione and pyrerubrine A. These natural compounds exhibit a diverse range of pharmacological effects, including antibacterial, antifungal, insecticidal, phytotoxic, anti-inflammatory, antimitotic, anti-diabetic, enzyme inhibitory, anticancer, cytoprotective, and ROS scavenging properties. It is worth noting that thujaplicane, a compound similar to tropolone, displays all of the listed biological activities except for antimitotic action, which has only been observed in one natural tropolone compound, colchicine. Tropolone can be synthesized from commercially available seven-membered rings or derived through various cyclization and cycloaddition reactions. Thailandepsin B, on the other hand, can be synthesized by macro-lactonization of the corresponding secoacid, followed by the formation of internal disulfide bonds. It is important to mention that thailandepsin B exhibits different selective inhibition profiles compared to FK228. Objective: We investigated the HDAC inhibitory activity of the Tropolones and Thailandepsin B and discussed the biosynthesis of the naturally occurring compounds and their synthetic scheme. Results and Conclusion: It has been observed that Tropolone derivatives act as isoenzyme-selective inhibitors of proven anticancer drug targets, histone deacetylases (HDACs). Some monosubstituted tropolones show remarkable levels of selectivity for HDAC2 and strongly inhibit the growth of T-lymphocyte cell lines. And Thailandepsins have different selective inhibition profiles than FK228. They exhibit comparable inhibitory activities to FK228 against human HDAC1, HDAC2, HDAC3, HDAC6, HDAC7, and HDAC9, but less potent inhibitory activities than FK228 toward HDAC4 and HDAC8, the latter of which may be useful. Thailandepsins possess potent cytotoxic activities toward some types of cell lines.

Protein acetylation is a reversible central mechanism to control gene expression and cell signaling events. Current evidence suggests that pharmacological inhibitors for protein deacetylation have already been used in various disease conditions. Accumulating reports showed that several compounds that enhance histone acetylation in cells are in both the preclinical and clinical development stages targeting non-communicable diseases, which include cancerous and non-cancerous especially cardiovascular complications. These compounds are, in general, enzyme inhibitors and target a family of enzymes- called histone deacetylases (HDACs). Since HDAC inhibitors have shown to be helpful in preclinical models of cardiac complications, further research on developing novel compounds with high efficacy and low toxicity may be essential for treating cardiovascular diseases. In this review, we have highlighted the roles of HDAC and its inhibitors in cardiac complications.

Background: Epigenetic regulation of gene signalling is one of the fundamental molecular mechanisms for the generation and maintenance of cellular memory. Histone acetylation is a common epigenetic mechanism associated with increased gene transcription in the central nervous system (CNS). Stimulation of gene transcription by histone acetylation is important for the development of CNS-based long-term memory. Histone acetylation is a target for cognitive enhancement via the application of histone deacetylase (HDAC) inhibitors. The promising potential of HDAC inhibitors has been observed in the treatment of several neurodevelopmental and neurodegenerative diseases. Objective: This study assessed the current state of HDAC inhibition as an approach to cognitive enhancement and treatment of neurodegenerative diseases. Our analysis provides insights into the mechanism of action of HDAC inhibitors, associated epigenetic priming, and describes the therapeutic success and potential complications after unsupervised use of the inhibitors. Results and Conclusion: Several chromatin-modifying enzymes play key roles in the regulation of cognitive processes. The importance of HDAC signaling in the brain is highlighted in this review. Recent advancements in the field of cognitive epigenetics are supported by the successful development of various HDAC inhibitors, demonstrating effective treatment of mood-associated disorders. The current review discusses the therapeutic potential of HDAC inhibition and observed complications after mood and cognitive enhancement therapies.

Background: The prevalence of drug-resistant organisms has steadily increased over the past few decades worldwide. Especially in tuberculosis (TB) disease, the problems of co-morbidity and the rapid emergence of multidrug resistance have necessitated the development of multitarget-based therapeutic regimens. Several multitargeting compounds against Mycobacterium tuberculosis (Mtb) have been studied through novel in silico tools but these have rendered reduced efficacy in clinical trials. The authors have focussed on many exotic targets belonging to crucial Mtb survival pathways whose molecular structures and functions are underexplored. Likewise, insights into the hidden possibilities of promiscuous compounds from natural products or repurposed drugs to inhibit other cellular proteins apart from their validated targets are also depicted in this review. In addition to the existing line of drugs currently recommended for multidrug-resistant TB, newer host-directed therapies could also be fruitful. Furthermore, several challenges, including safety/efficacy ratios of multitarget compounds highlighted here, can also be circumnavigated by researchers to design “smart drugs” for improved tuberculosis therapeutics. Conclusion: A holistic approach towards alleviating the existing drawbacks of drug discovery in drug-resistant TB has been outlined. Finally, considering the current needs, the authors have put forward an overall summary of possible trends in multitargeting that are significant for futuristic therapeutic solutions.