Synthesis and evaluation of new pyrazoline‐thiazole derivatives as monoamine oxidase inhibitors

A novel series of 1,3,5‐trisubstituted‐2‐pyrazoline derivatives ( 4a ‐ 4k ) was synthesized and their chemical structures characterized by ¹H NMR, ¹³C NMR, and mass spectroscopy. These compounds were evaluated as inhibitors for of type A and type B monoamine oxidase (MAO) enzymes. The most common inhibitors of MAO enzymes used to treat depression and anxiety such as selegiline and moclobemide drugs were used as reference agents. A result of biological evaluation of these compounds revealed compounds 4c , 4d , and 4? as potent and selective MAO A inhibitors. The most active compound 4? , which is 2,4‐dimethoxy at phenyl ring, showed strong inhibitory activity at MAO A (IC₅₀ of 0.0445 ± 0.0018μM). Furthermore, compounds 4c and 4d showed significant inhibition profile on MAO A with the IC₅₀ values 0.1423 ± 0.0051μM and 0.2148 ± 0.0067μM, respectively.     

Synthesis of new pyrazolone-based heterocycles as inhibitors of monoamine oxidase enzymes

A series of new substituted pyrazoles embedded with a variety of function groups has been synthesized from 4-[4-(1,2-dihydro-2,3-dimethyl-1-phenyl-5-oxo-3H-pyrazol-4-yl)]-2-cyano-4-oxo-butanenitrile (4). The synthesized compounds were fully characterized and their structures were elucidated based on elemental analysis, spectral data, and alternative synthetic pathways, whenever possible. The pharmacological activities of these new compounds as inhibitors for of type A and type B monoamine oxidase (MAO) enzymes have been investigated and compared to the most common inhibitors of MAO enzymes used to treat depression and anxiety such as deprenyl (selegiline), moclobemide, and clorgyline drugs. The most potent of the synthesized compounds was 4, 11, and 53 which showed higher inhibition activity toward type A MAO enzyme and even exceeded that of deprenyl, moclobemide, and clorgyline drugs.     

Synthesis and characterization of new thiadiazole derivatives bearing a pyrazole moiety

A series of thidiazole derivatives (4, 7) from pyrazole-3-carboxylic acid chloride (2) and pyrazole-3,4-dicarboxylic acid chloride derivatives (6) were synthesized and characterized. The structures of the new compounds were confirmed byelemental analysis, NMR (¹H and ¹³C) and IR spectra. The molecular and crystal structure of 4-benzoyl-N-[5-(methylthio)-1,3,4-thiadiazol-2-yl]-1,5-di-phenyl-1H-pyrazole-3-carboxamide(4d)was determined by single crystal X-ray diffraction method.     

Synthesis and evaluation of iodinated benzamide derivatives as selective and reversible monoamine oxidase B inhibitors.

A new series of iodinated analogues of N-(2-aminoethyl)benzamide was synthesized and evaluated for inhibitory potency and specificity toward monoamine oxidase type-B (MAO-B). Among them, N-(2-aminoethyl)-2-chloro-4-iodobenzamide hydrochloride (2d) showed high inhibitory potency and selectivity against MAO-B. The type of MAO-B inhibition by 2d was non-competitive and the inhibition constant (Ki) was 0.80 microM. Strong and selective in vivo MAO-B inhibition by 2d was also confirmed. The brain MAO-B inhibition by 2d was reversible and the enzyme activity completely returned to the control value 24 h after administration. Compound 2d was, therefore, considered to be a candidate for advanced development as a radioiodinated ligand that may be useful for functional MAO-B studies in the living brain using single photon emission computer tomography.     

Synthesis and antimicrobial activity evaluation of new dithiocarbamate derivatives bearing thiazole/benzothiazole rings

The synthesis of 2-(substituted phenyl)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithiodate (A1-A24) derivatives and 2-(4-substituted thiazol-2-ylamino)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithiodate (B1-B14) derivatives was undertaken starting from the potassium salt of 4-(2-pyrimidinyl)piperazine dithiocarbamate. The structures of the obtained compounds were elucidated by ¹H NMR, ¹³C NMR, MS spectral data, and elemental analysis. The antimicrobial activity of the thirty eight newly synthesized compounds were tested against 12 microorganism strains using the microdilution technique. Compounds 2-(4-ethoxycarbonylthiazol-2-ylamino)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithiodate (B12), 2-(3-fluorophenyl)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithiodate (A18) and 2-(3,4-difluorophenyl)-2-oxoethyl 4-(pyrimidin-2-yl)piperazin-1-carbodithiodate (A21) were determined to possess high antimicrobial activity.     

Liquid crystalline thiadiazole derivatives: new ferroelectric thiadiazole derivatives

A series of optically active thiadiazole Schiff's bases were prepared and their liquid crystalline properties were studied. Chirality was achieved by introducing an asymmetric carbon atom into the alkoxy group. Thus, 2-(p -active-alkoxyphenyl-imine)-5-(p-n-alkoxy)phenyl-1,3,4-thiadiazoles were synthesized. Their structures were characterized using elemental analysis, and IR, ¹H NMR and mass spectroscopies; their thermal properties were determined using DSC and polarized light microscopy. All the compounds are enantiotropic liquid crystals, and most of them exhibited both chiral smectic C^* and cholesteric mesophases. Only one of them did not show a smectic C^* phase.     

Liquid crystalline thiadiazole derivatives: new ferroelectric thiadiazole derivatives

A series of optically active thiadiazole Schiff's bases were prepared and their liquid crystalline properties were studied. Chirality was achieved by introducing an asymmetric carbon atom into the alkoxy group. Thus, 2-( p -active-alkoxyphenyl-imine)-5-( p - n -alkoxy)phenyl-1,3,4-thiadiazoles were synthesized. Their structures were characterized using elemental analysis, and IR, 1 H NMR and mass spectroscopies; their thermal properties were determined using DSC and polarized light microscopy. All the compounds are enantiotropic liquid crystals, and most of them exhibited both chiral smectic C* and cholesteric mesophases. Only one of them did not show a smectic C* phase.     

Synthesis and in vitro evaluation of new benzothiazole derivatives as schistosomicidal agents

A series of benzothiazol-2-yl-dithiocarbamates 3a-d along with their copper complexes 4a-c were synthesized via the reaction of suitable alkyl, aralkyl or heteroaryl halides with the sodium salt of benzothiazol-2-yl-dithiocarbamic acid, followed by complexation with copper sulphate. N-(4-Acetyl-5-aryl-4,5-dihydro-1,3,4-thiadiazol-2-yl)-N-benzothiazol-2-yl-acetamides 7a-c were synthesized by cyclization of the appropriate thiosemicarbazones 6a-c in acetic anhydride. Selected compounds were screened for in vitro schistosomicidal activity against Schistosoma mansoni at three different dosage levels (10, 50 and 100 microg/mL). Three of these products, 4a-c, showed schistosomicidal activity similar to praziquantel, with 100% worm mortality at 10 microg/mL. These compounds would constitute a new class of potent schistosomicidal agents.     

Synthesis and monoamine oxidase A/B inhibitory evaluation of new benzothiazole-thiazolylhydrazine derivatives

Abstract

In this study, a novel series of benzothiazole-thiazolylhydrazine (3a–3i) was synthesized and their structures were characterized by ¹H-NMR, ¹³C-NMR spectrometry, and mass spectroscopy. These compounds were evaluated as inhibitors of type A and type B monoamine oxidase (MAO) enzymes. The most active compound 3b (2-((2-(2-(4-(4-Nitrophenyl)thiazol-2-yl)hydrazineylidene)-2-phenylethyl)thio)benzothiazole) showed strong inhibitory activity at hMAO-A (IC₅₀ of 0.095?±?0.004?µM). Furthermore, compound 3i (2-((2-(2-(4-(2,4-dichlorophenyl)thiazol-2-yl)hydrazineylidene)-2-phenylethyl)thio)benzothiazole) showed significant inhibition profile on hMAO-A with the IC₅₀ values 0.141?±?0.006?µM.     

Synthesis and biological activities of benzothiazole derivatives bearing a 1,3,4-thiadiazole moiety

A series of benzothiazole derivatives bearing a 1,3,4-thiadiazole moiety were designed, synthesized and evaluated for their antibacterial, antifungal and antiviral activities. The bioassay results indicated that most of target compounds showed good antiviral activities against tobacco mosaic virus (TMV) and antibacterial activities against Xanthomonas oryzae pv. oryzae (Xoo) and Ralstonia solanacearum (Rs). Especially, the anti-Xoo effect of title compounds 5k (N-(5-methoxybenzo[d]thiazol-2-yl)-2-((5-(2-tolyl)-1,3,4-thiadiazol-2-yl)thio)acetamide) and the anti-Rs effect of title compounds 5a (N-(5-nitrobenzo[d]thiazol-2-yl)-2-((5-(4-(trifluorom ethyl)phenyl)-1,3,4-thiadiazol-2-yl)thio)acetmide) respectively reached 52.4% and 71.6% at 100?µg/mL, which are superior to that of bismerthiazol (32.0% and 52.3%). In addition, the protective and inactivation activities of title compound 5i (N-(5-methoxybenzo [d]thiazol-2-yl)-2-((5-(4-nitrophenyl)-1,3,4-thiadiazol-2-yl)thio)acetamide) against TMV were 79.5% and 88.3%, respectively, which are better than that of ningnanmycin (76.4% and 86.8%). The above research showed that benzothiazole derivatives bearing a 1,3,4-thiadiazole moiety may be used as potential molecular templates in searching for highly-efficient antiviral and antibacterial agents.     

Synthesis of new indoyl-1,3,4-oxadiazole and oxadiazine derivatives. Potential monoamine oxidase inhibitor activity

New indolyl-1,3,4-oxadiazole and oxadiazine derivatives were prepared as reversible monoamine oxidase inhibitors. The compound 5-(3-methylindolyl)-1,3,4-oxadiazol-2(3H)one was shown to be a good monoamine oxidase B inhibitor.     

Nitrogen heterocycles as potential monoamine oxidase inhibitors: Synthetic aspects

The present review highlights the synthetic methods of monoamine oxidase inhibitors (MAO) belonging to a group of nitrogen heterocycles such as pyrazoline, indole, xanthine, oxadiazole, benzimidazole, pyrrole, quinoxaline, thiazole and other related compounds (1990–2012). Moreover, it emphasizes salient findings related to chemical structures and the bioactivities of these heterocycles as MAO inhibitors. The aim of this review is to find out different methods for the synthesis of nitrogen containing heterocycles and their bioactivity related aspects as MAO inhibitors.     

Synthesis of new imidazole derivatives as potential inhibitors of thromboxane synthetase

The preparation of new imidazole derivatives containing a carboxylic moiety such as succinic, adipic or benzoic into the side chain, is reported starting from the suitable imidazole intermediates.     

Synthesis,monoamine oxidase inhibitory activity and computational study of novel isoxazole derivatives as potential antiparkinson agents

Monoamine oxidase (MAO) enzymes are one of the most promising targets for the treatment of neurological disorders. A series of phenylisoxazole carbohydrazides was designed, synthesized and screened for both MAO-A and MAO-B inhibition using Amplex Red assays. None of the compounds inhibited the MAO-A activity while most of them significantly inhibited MAO-B in the micromolar to nanomolar range. Among them, the compound N'-(4-methylbenzylidene)-5-phenylisoxazole-3-carbohydrazide (6c) exhibited the most potent inhibitory activity towards MAO-B. Enzyme kinetic studies revealed the reversible and competitive nature of compound 6c towards MAO-B inhibition. The results of the enzyme inhibition assay were in agreement with molecular docking study, in which compound 6c displayed a strong binding affinity for MAO-B with a docking score of -10.98 Kcal/mol. In order to explore the neuroprotective effect of compound 6c, MPTP-induced mouse model for Parkinson’s disease was used, and motor behavioural assessment of experimental animals was carried out. The compound 6c was able to significantly prevent the MPTP-induced neurotoxicity as revealed by improvement in gait behaviour in footprint test and increase in grip strength score in horizontal wire test. Thus, phenylisoxazole carbohydrazides can be promising leads in the development of potent, selective and reversible MAO-B inhibitors for the treatment of Parkinson’s disease.     

Synthesis of new imidazole derivatives as potential inhibitors of thromboxane synthetase. II

The preparation of new imidazole derivatives containing ether or amide functions into the side chain, is reported starting from the suitable imidazole intermediates.     

Synthesis,antimicrobial, antiquorum-sensing and cytotoxic activities of new series of benzothiazole derivatives

New series of benzothiazole derivatives were designed and synthesized. The newly synthesized compounds were screened for their antibacterial activity against Escherichia coli, Staphylococcus aureus and Bacillus cereus. Compounds 6j and 6o showed the highest activity against E. coli and S. aureus. The antifungal activity of these compounds was also tested against Candida albicans and Aspergillus fumigatus293. Compounds 4c, 4g and 6j exhibited the highest activity against C. albicans. In addition, compounds4 a and 6j displayed promising activity against A. fumigatus 293. The same compounds were examined for their antiquorum-sensing activity against Chromobacterium violaceum ATCC 12472, whereas compounds4 a, 6j and 6p showed moderate activity. The in vitro cytotoxicity testing of the synthesized compounds was performed against cervical cancer(Hela) and kidney fibroblast cancer(COS-7) cell lines. Results indicated that all tested compounds have IC50 values 50 mmol/L against both cell lines. Molecular properties, toxicities, drug-likeness, and drug score profiles of compounds 4a–c, 5a, 6g,h, 6j, 6l, 6o and7 c,d were also assessed.     

Synthesis and antiproliferative activity of novel A-homo-B-norsteroid thiadiazole derivatives

Using cholesterol as a starting material, two novel steroidal thiadiazole derivatives possessing a structure of A-homo lactam and a B-nor steroidal skeleton were designed and synthesized by six steps of reactions, and their antiproliferative activities were assayed against various cancer cell lines. The result shows that compound 7b displays an excellent selective inhibition to A-549 (human lung carcinoma) cancer cell lines with an IC₅₀ value of 8.0 μM.     

Binding models of reversible inhibitors to type-B monoamine oxidase

Interest in the inhibitors of type-B monoamine oxidase has grown in recent years, due to the evidence for multiple roles of one such agent (selegiline) in the pharmacological management of neurodegenerative disorders. A set of 130 reversible and selective inhibitors of MAO-B (including tetrazole, oxadiazolone, and oxadiazinone derivatives) were taken from the literature and subjected to a three-dimensional quantitative structure–activity relationship (3D-QSAR) study, using CoMFA and GOLPE procedures. The steric and lipophilic fields, alone and in combination, provided us with informative models and satisfactory predictions (q²=0.73). The validity of these models was checked against the 3D X-ray structure of human MAO-B. Flexible docking calculations, performed by using a new approach which took advantage from QXP and GRID computational tools, showed the diverse inhibitors to interact with MAO-B in a similar binding mode, irrespective of the heterocycle characterizing them. A significant trend of correlation was observed between estimated energies of the complexes and the experimental inhibition data.