ABSTRACT
A new series of 4-(3-nitrophenyl)thiazol-2-ylhydrazone derivatives were designed, synthesised, and evaluated to assess their inhibitory effect on the human monoamine oxidase (hMAO) A and B isoforms. Different (un)substituted (hetero)aromatic substituents were linked to N1 of the hydrazone in order to establish robust structure-activity relationships. The results of the biological testing demonstrated that the presence of the hydrazothiazole nucleus bearing at C4 a phenyl ring functionalised at the meta position with a nitro group represents an important pharmacophoric feature to obtain selective and reversible human MAO-B inhibition for the treatment of neurodegenerative disorders. In addition, the most potent and selective MAO-B inhibitors were evaluated in silico as potential cholinesterase (AChE/BuChE) inhibitors and in vitro for antioxidant activities. The results obtained from molecular modelling studies provided insight into the multiple interactions and structural requirements for the reported MAO inhibitory properties.
Subject(s)
Antioxidants/pharmacology , Hydrazones/pharmacology , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Thiazoles/pharmacology , Acetylcholinesterase/metabolism , Antioxidants/chemical synthesis , Antioxidants/chemistry , Butyrylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/chemistry , Cholinesterase Inhibitors/pharmacology , Humans , Hydrazones/chemical synthesis , Hydrazones/chemistry , Models, Molecular , Molecular Structure , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/chemistry , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
Bromodomain-containing proteins are epigenetic modulators involved in a wide range of cellular processes, from recruitment of transcription factors to pathological disruption of gene regulation and cancer development. Since the druggability of these acetyl-lysine reader domains was established, efforts were made to develop potent and selective inhibitors across the entire family. Here we report the development of a small molecule-based approach to covalently modify recombinant and endogenous bromodomain-containing proteins by targeting a conserved lysine and a tyrosine residue in the variable ZA or BC loops. Moreover, the addition of a reporter tag allowed in-gel visualization and pull-down of the desired bromodomains.
Subject(s)
Carbamates/chemistry , Histones/chemistry , Lysine/chemistry , Protein Domains , Pyridazines/chemistry , Triazoles/chemistry , Acetylation , Amino Acid Sequence , Binding Sites , Conserved Sequence , Molecular Docking Simulation , Protein BindingABSTRACT
A large number of novel secondary sulfonamides based on the open saccharin scaffold were synthesized and evaluated as selective inhibitors of four different isoforms of human carbonic anhydrase (hCA I, II, IX and XII, EC 4.2.1.1). They were obtained by reductive ring opening of the newly synthesized N-alkylated saccharin derivatives and were shown to be inactive against the two cytosolic off-target hCA I and II (Kis > 10 µM). Interestingly, these compounds inhibited hCA IX in the low nanomolar range with Kis ranging between 20 and 298 nM and were extremely potent inhibitors of hCA XII isoenzyme (Kis ranging between 4.3 and 432 nM). Since hCA IX and XII are the cancer-related isoforms recently validated as drug targets, these results represent an important goal in the development of new anticancer candidates. Finally, a computational approach has been performed to better correlate the biological data to the binding mode of these inhibitors.
Subject(s)
Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrases/drug effects , Neoplasms/enzymology , Protein Isoforms/drug effects , Saccharin/chemistry , Sulfonamides/chemistry , Humans , Molecular Structure , Spectrum Analysis/methodsABSTRACT
Carboxylates are the least investigated class of inhibitors of carbonic anhydrases (CAs). Here we explain the versatility of binding of these molecules to CAs by examining a new adduct of hCAâ II with N-carboxymethyl-saccharin.
Subject(s)
Carbonic Anhydrase II/chemistry , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrases/chemistry , Carboxylic Acids/chemistry , Saccharin/analogs & derivatives , Sulfonamides/chemistry , Binding Sites , Catalytic Domain , Crystallography, X-Ray , Models, Molecular , Saccharin/chemistryABSTRACT
Novel amide derivatives of Probenecid were synthesized and discovered to act as potent and selective inhibitors of the human carbonic anhydrase (hCA, EC 4.2.1.1) transmembrane isoforms hCA IX and XII. The proposed chemical transformation of the carboxylic acid into an amide group led to a complete loss of hCA I and II inhibition (Kis >10,000nM) and enhanced the inhibitory activity against hCA IX and XII, with respect to the parent compound (incorporating a COOH function). These promising biological results have been corroborated by molecular modelling studies within the active sites of the four studied human carbonic anhydrases, which enabled us to rationalize both the isoform selectivity and high activity against the tumor-associated isoforms hCA IX/XII.
Subject(s)
Antigens, Neoplasm/chemistry , Carbonic Anhydrase II/chemistry , Carbonic Anhydrase I/chemistry , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrases/chemistry , Probenecid/chemical synthesis , Carbonic Anhydrase IX , Carbonic Anhydrase Inhibitors/chemistry , Catalytic Domain , Crystallography, X-Ray , Enzyme Assays , Humans , Molecular Docking Simulation , Probenecid/analogs & derivatives , Protein Binding , Sensitivity and Specificity , Structure-Activity RelationshipABSTRACT
Several (thiazol-2-yl)hydrazone derivatives from 2-, 3- and 4-acetylpyridine were synthesized and tested against human monoamine oxidase (hMAO) A and B enzymes. Most of them had an inhibitory effect in the low micromolar/high nanomolar range, being derivatives of 4-acetylpyridine selective hMAO-B inhibitors also at low nanomolar concentrations. The structure-activity relationship, as confirmed by molecular modeling studies, proved that the pyridine ring linked to the hydrazonic nitrogen and the substituted aryl moiety at C4 of the thiazole conferred the inhibitory effects on hMAO enzymes. Successively, the strongest hMAO-B inhibitors were tested toward acetylcholinesterase (AChE) and the most interesting compound showed activity in the low micromolar range. Our results suggest that this scaffold could be further investigated for its potential multi-targeted role in the discovery of new drugs against the neurodegenerative diseases.
Subject(s)
Acetylcholinesterase/metabolism , Cholinesterase Inhibitors/chemical synthesis , Cholinesterase Inhibitors/pharmacology , Hydrazones/pharmacology , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Pyridines/chemistry , Pyridines/pharmacology , Thiazoles/pharmacology , Cholinesterase Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Hydrazones/chemical synthesis , Hydrazones/chemistry , Models, Molecular , Molecular Structure , Monoamine Oxidase Inhibitors/chemistry , Pyridines/chemical synthesis , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
A series of N-alkylated saccharin derivatives were synthesized and tested for the inhibition of four different isoforms of human carbonic anhydrase (CA, EC 4. 2.1.1): the transmembrane tumor-associated CA IX and XII, and the cytosolic CA I and II. Most of the reported derivatives inhibited CA XII in the nanomolar/low micromolar range, hCA IX with KIs ranging between 11 and 390 nM, whereas they were inactive against both CA I (KIs >50 µM) and II (K(I)s ranging between 39.1 nM and 50 µM). Since CA I and II are off-targets of antitumor carbonic anhydrase inhibitors (CAIs), the obtained results represent an encouraging achievement for the development of new anticancer candidates without the common side effects of non-selective CAIs. Moreover, the lack of an explicit zinc binding function on these inhibitors opens the way towards the exploration of novel mechanisms of inhibition that could explain the high selectivity of these compounds for the inhibition of the transmembrane, tumor-associated isoforms over the cytosolic ones.
Subject(s)
Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrases/metabolism , Drug Design , Saccharin/pharmacology , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Saccharin/chemical synthesis , Saccharin/chemistry , Structure-Activity RelationshipABSTRACT
Novel amide derivatives of probenecid, a well-known uricosuric agent, were synthesized and evaluated as inhibitors of human carbonic anhydrases (hCAs, EC 4.2.1.1). The transmembrane isoforms (hCA IX and XII) were potently and selectively inhibited by some of them. The proposed chemical modification led to a complete loss of hCA II inhibition (K(i)s>10,000 nM) and enhanced the inhibitory activity against the tumour-associated hCA XII (compound 4 showed a K(i) value of 15.3 nM). The enzyme inhibitory data have also been validated by docking studies of the compounds within the active site of hCA XII.
Subject(s)
Amides/chemistry , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrases/chemistry , Probenecid/chemistry , Amides/chemical synthesis , Amides/metabolism , Binding Sites , Carbonic Anhydrase II/antagonists & inhibitors , Carbonic Anhydrase II/metabolism , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrase Inhibitors/metabolism , Carbonic Anhydrases/metabolism , Catalytic Domain , Humans , Molecular Docking Simulation , Protein Binding , Structure-Activity Relationship , Sulfonamides/chemistryABSTRACT
Exploring the effect that substituents on the cycloaliphatic ring had on the inhibitory activity against human monoamine oxidase B of a series of 4-aryl-2-cycloalkylidenhydrazinylthiazoles led to the synthesis of a new series of 2-methylcyclopentyl and 3-methylcyclopentyl derivatives which were tested in vitro as mixtures of diastereoisomers. In fact, due to the presence of a chiral center on the cycloaliphatic ring and a trisubstituted CN bond, they exist as four diastereoisomers ((E)-(R), (E)-(S), (Z)-(R), (Z)-(S)). 4-(2,4-Difluorophenyl)-2-(2-(3-methylcyclopentylidene)hydrazinyl)thiazole was chosen as a model to investigate the influence of stereochemical requirements on the inhibitory activity against hMAO-B of these derivatives after a stereoconservative synthesis and semi-preparative HPLC diastereoseparation. (R)-(Z) isomer of this compound was endowed with a potent and selective hMAO-B inhibition higher than that of reference drugs as also corroborated by molecular modeling studies.
Subject(s)
Drug Design , Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Thiazoles/pharmacology , Chromatography, High Pressure Liquid , Dose-Response Relationship, Drug , Humans , Isoenzymes/antagonists & inhibitors , Isoenzymes/metabolism , Magnetic Resonance Spectroscopy , Models, Molecular , Molecular Structure , Monoamine Oxidase Inhibitors/chemical synthesis , Stereoisomerism , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
Monoamine oxidases (MAOs) are mitochondrial bound enzymes, which catalyze the oxidative deamination of monoamine neurotransmitters. Inside the brain, MAOs are present in two isoforms: MAO-A and MAO-B. The activity of MAO-B is generally higher in patients affected by neurodegenerative diseases like Alzheimer's and Parkinson's. Therefore, the search for potent and selective MAO-B inhibitors is still a challenge for medicinal chemists. Nature has always been a source of inspiration for the discovery of new lead compounds. Moreover, natural medicine is a major component in all traditional medicine systems. In this review, we present the latest discoveries in the search for selective MAO-B inhibitors from natural sources. For clarity, compounds have been classified on the basis of structural analogy or source: flavonoids, xanthones, tannins, proanthocyanidins, iridoid glucosides, curcumin, alkaloids, cannabinoids, and natural sources extracts. MAO inhibition values reported in the text are not always consistent due to the high variability of MAO sources (bovine, pig, rat brain or liver, and human) and to the heterogeneity of the experimental protocols used.
Subject(s)
Biological Products/pharmacology , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/metabolism , Animals , Biological Products/chemistry , Humans , Monoamine Oxidase Inhibitors/chemistry , Structure-Activity RelationshipABSTRACT
Salen and tetrahydrosalen derivatives possess metal-chelating properties and have been used as ligands in organic synthesis and as scaffolds for developing therapeutic agents. Fourteen such compounds were synthesized in order to explore their ability to inhibit the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). Human (h) isoforms hCA I, hCA II, hCA IX and hCA XII were included in the investigation. Several aliphatic and aromatic spacers were introduced between the two chelating groups from salen/tetrahydrosalen in order to explore a diverse chemical space for designing CA inhibitors, which incorporate both phenol and polyamine fragments in their molecule. Some of these compounds showed CA inhibitory activity in the low micromolar-nanomolar range and a pronounced selectivity for inhibiting an isoform over-expressed in hypoxic tumors, hCA XII, over hCA I, II and IX.
Subject(s)
Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrases/chemistry , Ethylenediamines/chemistry , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/metabolism , Carbonic Anhydrases/metabolism , Drug Design , Enzyme Activation/drug effects , Ethylenediamines/chemical synthesis , Ethylenediamines/metabolism , Humans , Neoplasms/enzymology , Neoplasms/pathology , Phenol/chemistry , Polyamines/chemistry , Protein Binding , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Structure-Activity RelationshipABSTRACT
A new scaffold of hydrazothiazoles has been designed as monoamine oxidase (MAO) inhibitors combining the hydrazine moiety of iproniazid and the thiazole nucleus of glitazones, a class of peroxisome proliferator-activated receptor (PPAR)γ agonists recently co-crystallized with human MAO-B. The resulting derivatives were synthesized and assayed to evaluate their in vitro activity against both the A and B isoforms of hMAO. All compounds were shown to be selective hMAO-B inhibitors with IC(50) values in the low micromolar/high nanomolar range. Such results suggest that the hydrazothiazole scaffold could be considered as an interesting pharmacophore for the future design of new lead compounds as coadjuvants for the treatment of neurodegenerative diseases.
Subject(s)
Hydrazines/pharmacology , Monoamine Oxidase Inhibitors/pharmacology , Monoamine Oxidase/drug effects , Thiazoles/pharmacology , Animals , Crystallization , Drug Design , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Heterocyclic Compounds/pharmacology , Humans , Hydrazines/chemical synthesis , Hydrazines/chemistry , Inhibitory Concentration 50 , Insecta/cytology , Monoamine Oxidase Inhibitors/chemical synthesis , Monoamine Oxidase Inhibitors/chemistry , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistryABSTRACT
Two series of saccharin/isoxazole and saccharin/isoxazoline hybrids were synthesized by 1,3-dipolar cycloaddition. The new compounds showed to be endowed with potent and selective inhibitory activity against the cancer-related human carbonic anhydrase (hCA) IX and XII isoforms in the nanomolar range, while no affinity was encountered for off-targets, such as hCA I and II. Successive enantioseparation on a milligram scale of the most representative compounds led to the discovery that (S)-isomers were more potent than their corresponding (R)-enantiomers. Lastly, molecular modeling studies were conducted to define those structural requirements that were responsible for the discrimination among selected human isoforms of carbonic anhydrases. Two nanomolar hCA IX and XII inhibitors were also screened for their selective toxicity against non tumoral primary cells (fibroblasts) and against a breast adenocarcinoma cell line (MCF7) in hypoxic environment. The efficacious combination of these compounds with doxorubicin on MCF7 cells was demonstrated after 72 h of treatment.
Subject(s)
Antigens, Neoplasm/metabolism , Carbonic Anhydrase IX/metabolism , Carbonic Anhydrase Inhibitors/chemistry , Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrases/metabolism , Saccharin/chemistry , Saccharin/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Carbonic Anhydrase IX/antagonists & inhibitors , Carbonic Anhydrase Inhibitors/chemical synthesis , Cell Line , Cycloaddition Reaction , Humans , Isoxazoles/chemical synthesis , Isoxazoles/chemistry , Isoxazoles/pharmacology , MCF-7 Cells , Molecular Docking Simulation , Neoplasms/drug therapy , Neoplasms/enzymology , Neoplasms/metabolism , Saccharin/chemical synthesisABSTRACT
With reference to recent studies reporting on the various biological properties of the thiazolidinone scaffold, we synthesized more than a hundred compounds characterized by a 1,3-thiazolidin-4-one nucleus derivatised at the C2 with a hydrazine bridge linked to (cyclo)aliphatic or hetero(aryl) moieties, and their N-benzylated derivatives. These molecules were assayed as potential anti-Candida agents and they were shown to possess comparable, and in some cases higher biological activity than well-established topical and systemic antimycotic drugs (i.e. clotrimazole, fluconazole, ketoconazole, miconazole, tioconazole, amphotericin B). Compounds endowed with the lowest MICs underwent further testing in order to assess their cytotoxic effect (CC50) on Hep2 cells, which demonstrated their relative safety. Finally, QSAR and 3-D QSAR models were used to predict putative chemical modifications of the 1,3-thiazolidin-4-one scaffold in order to design new and potential more active compounds against Candida spp.
Subject(s)
Antifungal Agents/chemical synthesis , Antifungal Agents/pharmacology , Thiazolidines/chemical synthesis , Thiazolidines/pharmacology , Antifungal Agents/chemistry , Candida/drug effects , Carbon-13 Magnetic Resonance Spectroscopy , Drug Screening Assays, Antitumor , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Hep G2 Cells , Humans , Microbial Sensitivity Tests , Proton Magnetic Resonance Spectroscopy , Quantitative Structure-Activity Relationship , Thiazolidines/chemistryABSTRACT
Despite the considerable interest in the search of new and potent human MAO inhibitors, an increasing number of research works deal with new therapeutic and analytical approaches regarding these molecules. Our interest was focused on the detailed analysis of (i) new pharmacological options for selective hMAO inhibitors; (ii) innovative analytical procedures to discover/screen hMAO inhibitors, and (iii) the recent possibility of using labeled hMAO inhibitors to unravel neurodegenerative diseases and drug distribution. All these three aspects could open new scenarios stimulating the interest of researchers in this field.
Subject(s)
Monoamine Oxidase Inhibitors/chemistry , Monoamine Oxidase Inhibitors/therapeutic use , Monoamine Oxidase , Binding Sites , Humans , Monoamine Oxidase/metabolism , Monoamine Oxidase Inhibitors/metabolism , Neurodegenerative Diseases/diagnostic imaging , Neurodegenerative Diseases/drug therapy , Neurodegenerative Diseases/enzymology , Neuroimaging/methods , Structure-Activity RelationshipABSTRACT
Antimitotic agents are widely used in cancer chemotherapy but the numerous side effects and the onset of resistance limit their clinical efficacy. Therefore, with the purpose of discovering more selective and efficient anticancer agents to be administered alone or in combination with traditional drugs, we synthesized a large library of 1,3,4-thiadiazoline analogues, maintaining the pharmacophoric structure of an antiproliferative compound known as K858: this is a new inhibitor of kinesin Eg5, able to induce the mitotic arrest in colorectal cancer cells and in xenograft ovarian cancer cells. We screened 103 compounds to assess their antiproliferative activity on PC3 prostate cancer cell line. Two derivatives, compounds 32 (corresponding to K858) and 33, have shown to be the most effective against prostate tumor cells and also towards two melanoma cell lines (SK-MEL-5 and SK-MEL-28) at low micromolar concentrations, confirming the pharmacological activity of this scaffold and revealing the potential role of 1,3,4-thiadiazolines in the management of cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Drug Evaluation, Preclinical , Enzyme Inhibitors/pharmacology , Melanoma/drug therapy , Prostatic Neoplasms/drug therapy , Small Molecule Libraries/pharmacology , Thiadiazoles/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Kinesins/antagonists & inhibitors , Kinesins/metabolism , Male , Melanoma/pathology , Mice , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Prostatic Neoplasms/pathology , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Structure-Activity Relationship , Thiadiazoles/chemical synthesis , Thiadiazoles/chemistryABSTRACT
We designed and synthesized a large number of novel thiazolidin-4-one derivatives for the evaluation of their anti-Toxoplasma gondii activity. This scaffold was functionalized at the N1-hydrazine portion with aliphatic, cycloaliphatic and (hetero)aromatic moieties. Then, a benzyl pendant was introduced at the lactamic NH of the core nucleus to evaluate the influence of this chemical modification on biological activity. The compounds were subjected to several in vitro assays to assess their anti-parasitic efficacy, cytotoxicity on fibroblasts, inhibition of tachyzoite invasion/attachment and replication after treatment. Results showed that fourteen of these thiazole-based compounds compare favorably to control compound trimethoprim in terms of parasite growth inhibition.
Subject(s)
Antiprotozoal Agents/pharmacology , Drug Design , Thiazolidines/pharmacology , Toxoplasma/drug effects , Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/chemistry , Dose-Response Relationship, Drug , Molecular Structure , Parasitic Sensitivity Tests , Structure-Activity Relationship , Thiazolidines/chemical synthesis , Thiazolidines/chemistryABSTRACT
Carbonic anhydrase (hCA) IX and XII isoforms are over-expressed both in primary and in metastatic cell lines of hypoxic tumors and are innovative targets for cancer diagnosis and treatment. On the basis of the importance of the pharmacophoric sulfamate moiety (bioisostere of the sulfonamide group) present in the structure of recent human CA inhibitors, we designed N-alkylated and O-alkylated derivatives of acesulfame, a cyclic tertiary sulfamate, assessing the inhibitory activity against the ubiquitous isoforms hCA I and II and the cancer-related isoforms hCA IX and XII. All derivatives were nanomolar inhibitors, with some of them possessing an outstanding selectivity towards the tumor-associated hCA IX and/or hCA XII isoforms.
Subject(s)
Carbonic Anhydrase Inhibitors/pharmacology , Carbonic Anhydrases/metabolism , Sulfonic Acids/pharmacology , Thiazines/pharmacology , Carbonic Anhydrase Inhibitors/chemical synthesis , Carbonic Anhydrase Inhibitors/chemistry , Dose-Response Relationship, Drug , Humans , Molecular Structure , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Structure-Activity Relationship , Sulfonic Acids/chemical synthesis , Sulfonic Acids/chemistry , Thiazines/chemical synthesis , Thiazines/chemistryABSTRACT
Recently we described some (thiazol-2-yl)hydrazones as antiprotozoal, antifungal and anti-MAO agents as well as Gcn5 HAT inhibitors. Among these last compounds, CPTH2 and CPTH6 showed HAT inhibition in cells and broad anticancer properties. With the aim to identify HAT inhibitors more potent than the two prototypes, we synthesized several new (thiazol-2-yl)hydrazones including some related thiazolidines and pyrimidin-4(3H)-ones, and we tested the whole library existing in our lab against human p300 and PCAF HAT enzymes. Some compounds (1x, 1c', 1d', 1i' and 2m) were more efficient than CPTH2 and CPTH6 in inhibiting the p300 HAT enzyme. When tested in human leukemia U937 and colon carcinoma HCT116 cells (100 µM, 30 h), 1x, 1i' and 2m gave higher (U937 cells) or similar (HCT116 cells) apoptosis than CPTH6, and were more potent than CPTH6 in inducing cytodifferentiation (U937 cells).
Subject(s)
Histone Acetyltransferases/antagonists & inhibitors , Hydrazones/chemistry , Hydrazones/pharmacology , Cell Line, Tumor , Drug Evaluation, Preclinical , HumansABSTRACT
A series of 4-substituted-2-thiazolylhydrazone derivatives have been synthesized and tested in vitro for their human monoamine oxidase (hMAO) A and B inhibitory activity. Our findings confirmed that the substitution at C4 of the thiazole ring was important to obtain highly potent and selective hMAO-B inhibitors with IC50 values in the nanomolar range. Moreover, these derivatives were endowed with a reversible mechanism of enzyme inhibition. Molecular modelling studies were performed to rationalize the recognition of all inhibitors with respect to hMAO-A and -B isoforms.