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

Cathepsin K (CatK) is a target for the treatment of osteoporosis, arthritis, and bone metastasis. Peptidomimetics with a cyanohydrazide warhead represent a new class of highly potent CatK inhibitors; however, their binding mechanism is unknown. We investigated two model cyanohydrazide inhibitors with differently positioned warheads: an azadipeptide nitrile Gü1303 and a 3-cyano-3-aza-β-amino acid Gü2602. Crystal structures of their covalent complexes were determined with mature CatK as well as a zymogen-like activation intermediate of CatK. Binding mode analysis, together with quantum chemical calculations, revealed that the extraordinary picomolar potency of Gü2602 is entropically favoured by its conformational flexibility at the nonprimed-primed subsites boundary. Furthermore, we demonstrated by live cell imaging that cyanohydrazides effectively target mature CatK in osteosarcoma cells. Cyanohydrazides also suppressed the maturation of CatK by inhibiting the autoactivation of the CatK zymogen. Our results provide structural insights for the rational design of cyanohydrazide inhibitors of CatK as potential drugs.

• MeSH
• hydraziny chemie   farmakologie   MeSH
• inhibitory proteas chemie   farmakologie   MeSH
• kathepsin K antagonisté a inhibitory   metabolismus   MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• nádorové buňky kultivované MeSH
• nitrily chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Hydrazide-hydrazones have been described as a scaffold with antimicrobial and cytotoxic activities as well as iodinated compounds. A resistance rate of bacterial and fungal pathogens has increased considerably. That is why we synthesized and screened twenty-two iodinated hydrazide-hydrazones 1 and 2, ten 1,2-diacylhydrazines 3 and their three reduced analogues 4 for their antibacterial, antifungal, and cytotoxic properties. Hydrazide-hydrazones were prepared by condensation of 4-substituted benzohydrazides with 2-/4-hydroxy-3,5-diiodobenzaldehydes, diacylhydrazines from identical benzohydrazides and 3,5-diiodosalicylic acid via its chloride. These compounds were investigated in vitro against eight bacterial and eight fungal strains. The derivatives were found potent antibacterial agents against Gram-positive cocci including methicillin-resistant Staphylococcus aureus with the lowest values of minimum inhibitory concentrations (MIC) of 7.81 μM. Four compounds inhibited also human pathogenic fungi (MIC of ≥1.95 μM). The derivatives had different degrees of cytotoxicity for HepG2 and HK-2 cell lines (IC50 values from 11.72 and 26.80 μM, respectively). Importantly, normal human cells exhibited lower sensitivity. The apoptotic effect was also investigated. In general, the presence of 3,5-diiodosalicylidene scaffold (compounds 1) is translated into enhanced both antimicrobial and cytotoxic properties whereas its 4-hydroxy isomers 2 share a low biological activity. N'-Benzoyl-2-hydroxy-3,5-diiodobenzohydrazides 3 have a non-homogeneous activity profile. Focusing on 4-substituted benzohydrazide part, the presence of an electron-withdrawing group (F, Cl, CF3, NO2) was found to be beneficial.

• MeSH
• antibakteriální látky chemie   farmakologie   MeSH
• antifungální látky chemie   farmakologie   MeSH
• Bacteria účinky léků   MeSH
• buňky Hep G2 MeSH
• houby účinky léků   MeSH
• hydraziny chemie   MeSH
• hydrazony chemie   MeSH
• lidé MeSH
• objevování léků MeSH
• protinádorové látky chemie   farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Twelve 7-chloroquinoline derivatives were designed and synthesized using the principle of molecular hybridization through the coupling of 2-[2-(7-chloroquinolin-4-ylthio)-4-methylthiazol-5-yl]acetic acid 1 with various benzoyl hydrazines 2a-l. The synthetic compounds were tested as antimalarials. Some of them showed an efficient in vitro activity as inhibitors of β-hematin formation and an in vivo activity in a murine model, resulting in compounds 8 and 9 as the most active ones with IC50 values of 0.65 ± 0.09 and 0.64 ± 0.16 µM, respectively. The effects of the compounds on the cell viability, cell cycle, and apoptosis induction of A549 and MCF-7 cancer cell lines were also examined. Our data showed that compounds 6 and 12 were the most active agents, decreasing the cell viability of MCF-7 cells with IC50 values of 15.41 and 12.99 µM, respectively. None of the compounds analyzed significantly affected the viability of peripheral blood mononuclear cells. Also, significant induction of apoptosis was observed when both cancer cell lines were incubated with compounds 6 and 12. In MCF-7 cells, treatment with these compounds led to cell cycle arrest in the G0/G1 phase. The results obtained suggest that these structures may be useful in developing new therapies for malaria and cancer treatment.

• MeSH
• antimalarika chemická syntéza   chemie   farmakologie   MeSH
• apoptóza účinky léků   MeSH
• buňky A549 MeSH
• chinoliny chemická syntéza   chemie   farmakologie   MeSH
• hydraziny chemická syntéza   chemie   farmakologie   MeSH
• inhibiční koncentrace 50 MeSH
• kontrolní body buněčného cyklu účinky léků   MeSH
• kyselina octová chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• malárie farmakoterapie   MeSH
• MFC-7 buňky MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• thiazoly chemická syntéza   chemie   farmakologie   MeSH
• viabilita buněk účinky léků   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Based on the broad spectrum of biological activity of hydrazide-hydrazones, trifluoromethyl compounds, and clinical usage of cholinesterase inhibitors, we investigated hydrazones obtained from 4-(trifluoromethyl)benzohydrazide and various benzaldehydes or aliphatic ketones as potential inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). They were evaluated using Ellman's spectrophotometric method. The hydrazide-hydrazones produced a dual inhibition of both cholinesterase enzymes with IC50 values of 46.8-137.7 µM and 19.1-881.1 µM for AChE and BuChE, respectively. The majority of the compounds were stronger inhibitors of AChE; four of them (2-bromobenzaldehyde, 3-(trifluoromethyl)benzaldehyde, cyclohexanone, and camphor-based 2o, 2p, 3c, and 3d, respectively) produced a balanced inhibition of the enzymes and only 2-chloro/trifluoromethyl benzylidene derivatives 2d and 2q were found to be more potent inhibitors of BuChE. 4-(Trifluoromethyl)-N'-[4-(trifluoromethyl)benzylidene]benzohydrazide 2l produced the strongest inhibition of AChE via mixed-type inhibition determined experimentally. Structure-activity relationships were identified. The compounds fit physicochemical space for targeting central nervous systems with no apparent cytotoxicity for eukaryotic cell line together. The study provides new insights into this CF3-hydrazide-hydrazone scaffold.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• centrální nervový systém účinky léků   MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• hematoencefalická bariéra účinky léků   patologie   MeSH
• hydraziny chemie   MeSH
• hydrazony chemie   farmakologie   MeSH
• kinetika MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Pluripotent stem cells of the bone marrow are stimulated by different cytokines to proliferation and differentiation into various types of blood cells. These cytokines are mostly glycoproteins. Erythropoietin stimulates stem cells to the formation of erythrocytes while colony-stimulating factors cause the formation of different types of white blood cells. Stem cell factors play an important role in the maintenance and survival of blood cells of all types. Thrombopoietin stimulates stem cells to proliferation and formation of blood platelets. Granulocyte colony-stimulating factor is probably the most important drug in use. It stimulates stem cells to the formation of neutrophile granulocytes. It is often used in recombinant forms such as filgrastim in the treatment of neutropenia in cancer chemotherapy or AIDS. Its pegylated conjugates such as pegfilgrastim are also available. Its activity can be supported by plerixafor, a small molecule - bicyclam derivative acting as an indirect agonist of stem cells factor. It acts as an antagonist of CXCR4 receptor activation of which brakes hematopoiesis. The treatment of conditions accompanied by thrombocytopenia such as idiopathic thrombocytopenic purpura is currently not performed by thrombopoietin but synthetic agonists of its receptor are preferred. Romiplostim is a peptibody. It consists of a protein part interacting with the thrombopoietin receptor which is, however, different from thrombopoietin, and of Fc fragment of immunoglobulin G1. In contrast, small molecule thrombopoietin receptor agonists represented by eltrombopag can be given orally unlike all of the above.

• MeSH
• benzoáty chemie   farmakologie   MeSH
• buněčná diferenciace účinky léků   MeSH
• faktory stimulující kolonie farmakologie   MeSH
• hydraziny chemie   farmakologie   MeSH
• knihovny malých molekul chemie   farmakologie   MeSH
• leukocyty mononukleární cytologie   účinky léků   metabolismus   MeSH
• lidé MeSH
• pyrazoly chemie   farmakologie   MeSH
• receptory thrombopoetinu agonisté   metabolismus   MeSH
• růstový faktor kmenových buněk farmakologie   MeSH
• trombocyty cytologie   metabolismus   MeSH
• trombopoéza účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Chitosan and β-glucan are substances that are very widely used in the pharmaceutical and food industries, medicine and other areas. These polysaccharides have immense significance in human metabolism. They are able to affect the levels of cholesterol and lipids. Chemical modification of these polysaccharides allows the support of these attributes. A main goal is to prepare a group of amide derivatives of carboxymethyl chitosan and carboxymethyl β-glucan to obtain a new group of polysaccharide derivatives and increase the benefits and attributes of these polysaccharides. The aim of carboxymethylation and subsequent two-step amidation is to achieve a high degree of substitution in the prepared derivatives. The amidation consisted methyl esterification followed by amino-de-alkoxylation with amidation reagents (n-alkylamines, hydrazine and hydroxylamine). The purity and substitution degree of the prepared derivatives were monitored by vibration spectroscopic methods (FTIR and FT Raman) and organic elemental analysis. The main, which was due to the presence of a secondary component (chitin) of polysaccharides, was the calculation of the substitution degree, which was based on the organic elemental analysis in combination with FTIR spectroscopy. These analytic methods confirmed the preparation of the substituted N-alkylamides, hydrazide and hydroxamic acid of carboxymethyl chitosan and carboxymethyl β-glucan.

• MeSH
• beta-glukany chemie   MeSH
• chitin chemie   MeSH
• chitosan analogy a deriváty   chemie   MeSH
• esterifikace MeSH
• hydraziny chemie   MeSH
• hydrofobní a hydrofilní interakce MeSH
• lidé MeSH
• polysacharidy chemie   MeSH
• spektroskopie infračervená s Fourierovou transformací metody   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

BACKGROUND: Hydrazide-hydrazones have been known as scaffold with various biological activities including inhibition of acetyl- (AChE) and butyrylcholinesterase (BuChE). Cholinesterase inhibitors are mainstays of dementias' treatment. OBJECTIVE: Twenty-five iodinated hydrazide-hydrazones and their analogues were designed as potential central AChE and BuChE inhibitors. METHODS: Hydrazide-hydrazones were synthesized from 4-substituted benzohydrazides and 2-/4- hydroxy-3,5-diiodobenzaldehydes. The compounds were investigated in vitro for their potency to inhibit AChE from electric eel and BuChE from equine serum using Ellman's method. We calculated also physicochemical and structural parameters for CNS delivery. RESULTS: The derivatives exhibited a moderate dual inhibition with IC50 values ranging from 15.1-140.5 and 35.5 to 170.5 μmol.L-1 for AChE and BuChE, respectively. Generally, the compounds produced a balanced or more potent inhibition of AChE. N'-[(E)-(4-Hydroxy-3,5-diiodophenyl)methylidene]-4- nitrobenzohydrazide 2k and 4-fluoro-N'-(2-hydroxy-3,5-diiodobenzyl)benzohydrazide 3a were the most potent inhibitors of AChE and BuChE, respectively. Structure-activity relationships were established, and molecular docking studies confirmed interaction with enzymes. CONCLUSION: Many novel hydrazide-hydrazones showed lower IC50 values than rivastigmine against AChE and some of them were comparable for BuChE to this drug used for the treatment of dementia. They interact with cholinesterases via non-covalent binding into the active site. Based on the BOILEDEgg approach, the majority of the derivatives met the criteria for blood-brain-barrier permeability.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• Electrophorus MeSH
• hydraziny chemická syntéza   chemie   farmakologie   MeSH
• hydrazony chemická syntéza   chemie   farmakologie   MeSH
• koně MeSH
• molekulární struktura MeSH
• simulace molekulového dockingu MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Herein we describe the design and synthesis of two series of sulfonamides featuring N-unsubstituted (4a-c) or N-substituted (7a-o) isatin moieties (as tails) connected to benzenesulfonamide moiety via a hydrazine linker. All the prepared sulfonamides (4a-c and 7a-o) showed potent inhibitory activities toward transmembrane tumor-associated human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, IX and XII with KI range (8.3-65.4 nM) and (11.9-72.9 nM), respectively. Furthermore, six sulfonamides (7e, 7i, 7j, 7m, 7n and 7o) were assessed for their anti-proliferative activity, according to US-NCI protocol, toward a panel of sixty cancer cell lines. Compounds 7j and 7n were the most promising counterparts in this assay displaying broad spectrum anti-proliferative activity toward diverse cell lines. Also, sulfonamide 7n significantly inhibited clonogenicity of HCT-116 cells in a concentration dependent manner in the colony forming assay. Moreover, molecular modeling studies were performed to gain insights for the plausible binding interactions and affinities for the target isatin-based sulfonamides (4a-c and 7a-o) within hCA isoforms II and IX active sites.

• MeSH
• hydraziny chemie   farmakologie   MeSH
• inhibitory karboanhydras chemická syntéza   chemie   farmakologie   MeSH
• isatin chemie   farmakologie   MeSH
• karboanhydrasy metabolismus   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buňky kultivované MeSH
• proliferace buněk účinky léků   MeSH
• protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• screeningové testy protinádorových léčiv MeSH
• simulace molekulového dockingu MeSH
• sulfonamidy chemická syntéza   chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

AIM: From betulinic acid (1a), we synthesized 30-oxobetulinic acid (2a) that is highly cytotoxic against many cancer cell lines; however, its generic toxicity is the main obstacle in further development as cytostatic. Methodology & results: From 2a, we prepared a new class of compounds - nonsymmetrical azines and tested their in vitro cytotoxicity. All new azines with a free 28-COOH group (4a-4e) were highly and selectively cytotoxic against the T-lymphoblastic leukemia cell line CCRF-CEM and exhibited dose-dependent inhibition of RNA and DNA synthesis and other cell-cycle alterations, including the M-phase block. CONCLUSION: The potential use of azines (4a-4e) in drug development focused on hematological cancers is significantly higher than that of previously studied acids 1a and 2a.

• MeSH
• buněčné linie MeSH
• fytogenní protinádorové látky chemická syntéza   chemie   farmakologie   MeSH
• hydraziny chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární konformace MeSH
• proliferace buněk účinky léků   MeSH
• screeningové testy protinádorových léčiv MeSH
• triterpeny chemická syntéza   chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH