Aim: 2-Thioxothiazolidin-4-one represents a versatile scaffold in drug development. The authors used it to prepare new potent acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors that can be utilized, e.g., to treat Alzheimer's disease. Materials & methods: 3-Amino-2-thioxothiazolidin-4-one was modified at the amino group or active methylene, using substituted benzaldehydes. The derivatives were evaluated for inhibition of AChE and BChE (Ellman's method). Results & conclusion: The derivatives were obtained with yields of 52-94%. They showed dual inhibition with IC50 values from 13.15 μM; many compounds were superior to rivastigmine. The structure-activity relationship favors nitrobenzylidene and 3,5-dihalogenosalicylidene scaffolds. AChE was inhibited noncompetitively, whereas BChE was inhibited with a mixed type of inhibition. Molecular docking provided insights into molecular interactions. Each enzyme is inhibited by a different binding mode.
Hydrazinecarboxamides (semicarbazides) are increasingly recognized as a versatile scaffold in developing potential antimicrobial agents. In addition to a brief overview of the synthetic methods to prepare them, this review comprehensively analyses their antimicrobial properties. These derivatives have demonstrated potent activity against a broad spectrum of mycobacteria, bacterial and fungal pathogens, highlighting their potential to address critical human health challenges, including neglected diseases, and to combat growing antimicrobial resistance. They have also been investigated for their antiviral and antiparasitic properties. The review also summarizes structure-activity relationships, known mechanisms of action and emphasizes the crucial role of the hydrazinecarboxamide moiety in facilitating interactions with biological targets. The combination of hydrazinecarboxamides with other bioactive scaffolds (primaquine, isoniazid, etc.) has led to an identification of promising drug candidates, including those active against resistant strains, offering a promising approach for future innovations in the field of antimicrobial therapy. Attention is also drawn to limitations of hydrazinecarboxamides (poor physicochemical properties, cytotoxicity to human cells, and insufficient target selectivity), which may hinder their clinical application.
- MeSH
- antiinfekční látky * farmakologie chemie MeSH
- Bacteria účinky léků MeSH
- lidé MeSH
- semikarbazidy * farmakologie chemie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
This review comprehensively summarizes recent advances in the field of hydrazinecarboxamide (semicarbazide) derivatives, highlighting their significant therapeutic potential and a broad spectrum of biological activities. As a promising and privileged scaffold in medicinal chemistry, hydrazinecarboxamides have emerged as a versatile class of compounds with significant bioactive properties. Based on their substitutions, their structural diversity permits extensive chemical modifications to enhance their interactions with various biological targets to combat multiple disorders. Notable, this group of compounds has shown significant efficacy against numerous cancer cell lines through diverse mechanisms of action and potent inhibition of enzymes, including cholinesterases, carbonic anhydrases, cyclooxygenases, lipoxygenases, etc. Beyond these, they have also been investigated for their anticonvulsive, analgesic/anti-inflammatory, and antioxidant properties, with detailed structure-activity relationships. For many applications, the hybridization of hydrazinecarboxamides with other bioactive scaffolds, such as primaquine, is of particular interest and offers advantages. Despite their promises, challenges such as suboptimal physicochemical properties and selectivity issues of certain derivatives require further effort. The review aims to inspire future innovation in the design and development of new potential hydrazinecarboxamide-based drugs, addressing existing challenges and expanding their therapeutic applications.
- MeSH
- antiflogistika farmakologie chemie MeSH
- antikonvulziva * farmakologie chemie MeSH
- antioxidancia * farmakologie chemie MeSH
- hydraziny * chemie farmakologie chemická syntéza MeSH
- inhibitory enzymů farmakologie chemie chemická syntéza MeSH
- lidé MeSH
- molekulární struktura MeSH
- protinádorové látky * farmakologie chemie MeSH
- semikarbazidy chemická syntéza chemie farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Increasing resistance in Staphylococcus aureus has created a critical need for new drugs, especially those effective against methicillin-resistant strains (methicillin-resistant Staphylococcus aureus [MRSA]). Sulfonamides are a privileged scaffold for the development of novel antistaphylococcal agents. This review covers recent advances in sulfonamides active against MRSA. Based on the substitution patterns of sulfonamide moieties, its derivatives can be tuned for desired properties and biological activity. Contrary to the traditional view, not only N-monosubstituted 4-aminobenzenesulfonamides are effective. Novel sulfonamides have various mechanisms of action, not only 'classical' inhibition of the folate biosynthetic pathway. Some of them can overcome resistance to classical sulfa drugs and cotrimoxazole, are bactericidal and active in vivo. Hybrid compounds with distinct bioactive scaffolds are particularly advantageous.
Aldose reductase, the first enzyme of the polyol pathway represents a key drug target in therapy of diabetic complications. In this study a series of six novel rhodanine based inhibitors of aldose reductase was designed, synthesized, and tested for their ability to inhibit aldose reductase and for selectivity relative to structurally related aldehyde reductase. Aldose reductase inhibitory activities of the compounds were characterized by the IC50 values ranging from 2000 nM to 20 nM. The values of selectivity factors relative to aldehyde reductase were decreasing in the same array from 24 to 5. In silico docking into the inhibitor binding site of aldose reductase revealed a specific binding pattern of the compounds comprising interaction of the deprotonated 4-hydroxybenzylidene group with the anion-binding sub-pocket of aldose reductase, creating a strong H-bond and charge interactions. Predicted pH-distribution profiles of the novel compounds into octanol, supported by experimentally determined distribution ratios, favour drug uptake at the physiological pH, as a result of the presence of the low-acidic phenolic group, instead of the more acidic carboxymethyl functional group.
- MeSH
- aldehydreduktasa MeSH
- inhibitory enzymů * chemie MeSH
- rhodanin * farmakologie chemie MeSH
- vazebná místa MeSH
- Publikační typ
- časopisecké články MeSH
Background: Molecular hybridization and isostery are proven approaches in medicinal chemistry, and as such we used them to design novel compounds that we investigated as potential antimycobacterials to combat drug-resistant strains. Methods & results: Prepared N-alkyl-2-(pyrimidine-5-carbonyl)hydrazine-1-carboxamides were cyclized to N-alkyl-5-(pyrimidin-5-yl)-1,3,4-oxadiazol-2-amines along with their analogues. A total of 48 compounds were tested against Mycobacterium tuberculosis H37Rv, Mycobacterium avium and Mycobacterium kansasii, with oxadiazoles and C8-C12 alkyls being the most effective from a concentration of 2 μM. Multidrug-resistant strains were inhibited at same concentrations as the susceptible strain. For the most potent N-dodecyl-5-(pyrimidin-5-yl)-1,3,4-oxadiazol-2-amine, the mechanism of action related to cell wall biosynthesis was investigated. Conclusion: Pyrimidine-1,3,4-oxadiazole hybrids are unique antimycobacterial agents inhibiting mainly M. tuberculosis strains without cross-resistance to current drugs and are thus promising drug candidates.
- MeSH
- aminy farmakologie MeSH
- antibakteriální látky * farmakologie MeSH
- antituberkulotika farmakologie chemie MeSH
- mikrobiální testy citlivosti MeSH
- Mycobacterium tuberculosis * MeSH
- oxadiazoly farmakologie chemie MeSH
- pyrimidiny farmakologie MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Phenotypic screening of an in-house library of small molecule purine derivatives against Mycobacterium tuberculosis (Mtb) led to the identification of 2-morpholino-7-(naphthalen-2-ylmethyl)-1,7-dihydro-6H-purin-6-one 10 as a potent antimycobacterial agent with MIC99 of 4 μM. Thorough structure-activity relationship studies revealed the importance of 7-(naphthalen-2-ylmethyl) substitution for antimycobacterial activity, yet opened the possibility of structural modifications at positions 2 and 6 of the purine core. As the result, optimized analogues with 6-amino or ethylamino substitution 56 and 64, respectively, were developed. These compounds showed strong in vitro antimycobacterial activity with MIC of 1 μM against Mtb H37Rv and against several clinically isolated drug-resistant strains, had limited toxicity to mammalian cell lines, medium clearance with respect to phase I metabolic deactivation (27 and 16.8 μL/min/mg), sufficient aqueous solubility (>90 μM) and high plasma stability. Interestingly, investigated purines, including compounds 56 and 64, lacked activity against a panel of Gram-negative and Gram-positive bacterial strains, indicating a specific mycobacterial molecular target. To investigate the mechanism of action, Mtb mutants resistant to hit compound 10 were isolated and their genomes were sequenced. Mutations were found in dprE1 (Rv3790), which encodes decaprenylphosphoryl-β-d-ribose oxidase DprE1, enzyme essential for the biosynthesis of arabinose, a vital component of the mycobacterial cell wall. Inhibition of DprE1 by 2,6-disubstituted 7-(naphthalen-2-ylmethyl)-7H-purines was proved using radiolabelling experiments in Mtb H37Rv in vitro. Finally, structure-binding relationships between selected purines and DprE1 using molecular modeling studies in tandem with molecular dynamic simulations revealed the key structural features for effective drug-target interaction.
- MeSH
- alkoholoxidoreduktasy chemie MeSH
- antituberkulotika * chemie MeSH
- bakteriální proteiny metabolismus MeSH
- Mycobacterium tuberculosis * MeSH
- puriny farmakologie MeSH
- savci metabolismus MeSH
- simulace molekulární dynamiky MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
In this study, we have focused on a multiparametric microbiological analysis of the antistaphylococcal action of the iodinated imine BH77, designed as an analogue of rafoxanide. Its antibacterial activity against five reference strains and eight clinical isolates of Gram-positive cocci of the genera Staphylococcus and Enterococcus was evaluated. The most clinically significant multidrug-resistant strains, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant S. aureus (VRSA), and vancomycin-resistant Enterococcus faecium, were also included. The bactericidal and bacteriostatic actions, the dynamics leading to a loss of bacterial viability, antibiofilm activity, BH77 activity in combination with selected conventional antibiotics, the mechanism of action, in vitro cytotoxicity, and in vivo toxicity in an alternative animal model, Galleria mellonella, were analyzed. The antistaphylococcal activity (MIC) ranged from 15.625 to 62.5 μM, and the antienterococcal activity ranged from 62.5 to 125 μM. Its bactericidal action; promising antibiofilm activity; interference with nucleic acid, protein, and peptidoglycan synthesis pathways; and nontoxicity/low toxicity in vitro and in vivo in the Galleria mellonella model were found to be activity attributes of this newly synthesized compound. In conclusion, BH77 could be rightfully minimally considered at least as the structural pattern for future adjuvants for selected antibiotic drugs. IMPORTANCE Antibiotic resistance is among the largest threats to global health, with a potentially serious socioeconomic impact. One of the strategies to deal with the predicted catastrophic future scenarios associated with the rapid emergence of resistant infectious agents lies in the discovery and research of new anti-infectives. In our study, we have introduced a rafoxanide analogue, a newly synthesized and described polyhalogenated 3,5-diiodosalicylaldehyde-based imine, that effectively acts against Gram-positive cocci of the genera Staphylococcus and Enterococcus. The inclusion of an extensive and comprehensive analysis for providing a detailed description of candidate compound-microbe interactions allows the valorization of the beneficial attributes linked to anti-infective action conclusively. In addition, this study can help with making rational decisions about the possible involvement of this molecule in advanced studies or may merit the support of studies focused on related or derived chemical structures to discover more effective new anti-infective drug candidates.
- MeSH
- antibakteriální látky farmakologie chemie MeSH
- antiinfekční látky * farmakologie MeSH
- Enterococcus MeSH
- methicilin rezistentní Staphylococcus aureus * MeSH
- mikrobiální testy citlivosti MeSH
- rafoxanid farmakologie MeSH
- Staphylococcus aureus MeSH
- Staphylococcus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
