Novel thiazole‐piperazine derivatives as potential cholinesterase inhibitors

Dementia is a cognitive disorder mostly associated with Alzheimer's disease (AD) in addition to being seen in many other diseases of the central nervous system (CNS). The limited number of drugs is not sufficient to provide adequate improvement to increase the quality of life of patients suffering from this symptom; therefore, all treatment options should be evaluated in detail. In this study, new molecules, [2‐(4‐(2/3/4‐substituted phenyl)piperazin‐1‐yl)‐4‐phenylthiazol‐5‐yl][3/4‐substituted phenyl]methanone derivatives ( 1‐44 ), were obtained and analyzed in terms of their anticholinesterase activities. Kinetic mode and molecular interactions were also evaluated. An enzyme inhibition study was undertaken on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) using the Ellman method. Maestro program was used in molecular modeling studies. Forty‐four compounds were evaluated on AChE and BChE enzymes at 10^?3 and 10^?4 concentrations. The inhibition concentrations were calculated as 0.268μM to 2.104μM for six compounds ( 4 , 5 , 16 , 27 , 37 , and 38 ) on AChE. Compound 5 including the 4‐methoxy substituent (IC₅₀: 0.268μM) and compound 38 containing the 4‐methoxy and 3‐methyl substituents (IC₅₀: 0.286μM) showed the highest AChE inhibitory activity. They were further examined in terms of hydrogen bonding with Arg296 and Ar‐Ar interaction with Trp286. The activity of compound 5 was also assessed in mixed‐type kinetic mode.     

Synthesis,docking and ADME prediction of novel 1,2,3-triazole-tethered coumarin derivatives as potential neuroprotective agents

Research on Chemical Intermediates - In an attempt to find potential neuroprotective agents, a series of novel 3-(1-((1-(substituted phenyl)-1H-1,2,3-triazol-4-yl) methoxyimino)...     

Synthesis of sydnonimine derivatives as potential trypanocidal agents

N‐(p‐Nitrophenoxy)carbonyl‐3‐morpholino‐sydnonimine (NCMS) has been prepared from 3‐morpholinosydnonimine hydrochloride. Using the Griess assay and the superoxide‐mediated reduction of ferricytochrome c, the nitric oxide (NO?) and superoxide anion (O₂?^‐) ‐ releasing properties in phosphate buffer pH 7.4 of this novel peroxynitrite donor was studied and compared with the known 3‐morpholino‐sydnonimine (SIN‐1). From compound NCMS, a series of N‐substituted sydnonimine derivatives were easily prepared that contain purine or melaminophenyl groups which specify a recognition by a trypanosomal purine transporter. The ability of these new sydnonimines to inhibit the uptake of [2³H]adenosine on Trypanosoma equiperdum was studied.     

Anabasine and cytisine derivatives as reversible cholinesterase inhibitors

A number of analogs of acetyl--methylcholine, containing residues of the alkaloids anabasine and cytisine as cyclic ammonium groupings, have been synthesized. The structures of the substances obtained have been confirmed by their IR and PMR spectra and the result of elementary analysis. The kientic parameters of the interaction of the compounds synthesized with acetylcholinesterase (ACE) of human blood erythrocytes and with butylcholinesterase (BuCE) of horse blood serum have been investigated. All the substances synthesized proved to be reversible inhibitors of ACE and BuCE.Institute of Bioorganic Chemistry, Academy of Sciences of the Uzbek SSR, Tashkent. Translated from Khimiya Prirodnykh Soedinenii, No. 1, pp. 97–100, January–February, 1988.     

Synthesis of 2-thiobenzimidazole derivatives as potential antifilarial agents

Several 5-benzoyl-2-thiobenzimidazole and 2-thiobenzimidazole aliphatic acids, esters, and N,N-dialkyl-carboxamides and thiocarboxamides were prepared by reacting bromo aliphatic acids, bromo aliphatic esters, and N,N-dialkylcarbamoyl or thiocarbamoyl chlorides with 5-benzoyl-2-thiobenzimidazole or 2-thiobenzimidazole in the presence of base. 2-Thiocarbomethoxy- and 2-thiocarboethoxybenzimidazole were prepared by the reaction of 2-thiobenzimidazole with methyl or ethyl chloroformate in the presence of base. However, the reaction of 5-benzoyl-2-thiobenzimidazole with ethyl chloroformate, afforded 5-benzoyl-2-ethylthiobenz-imidazole.     

Synthesis of 2-quinolinecarboxamide derivatives as potential HDAC inhibitors

Inhibition of histone deacetylase activity appears as an original and effective approach for the treatment of cancer. A series of novel quinoline-containing derivatives has been synthesized and found that some of these compounds possess nanomolar histone deacetylase inhibitory activity.     

Synthesis of pyrazole derivatives as potential bioisosteres of thromboxane-synthetase inhibitors

A series of ω-carboalkenyl pyrazole derivatives have been synthesized as potential thromboxane-synthetase inhibitors considering the close bioisosteric relationship between the pyrazole ring and other heteroaromatic carboalkenyl compounds exhibiting inhibitory activity. (E)-7-(1-Phenylpyrazol-4-yl)hept-2-enoic acid (4b) were prepared in 28% overall yield from its minor bis-homologue, (E)-5-(1-phenylpyrazol-4-yl)pent-2-enoic acid (4a) , obtained from 4-formyl-1-phenylpyrazole (6) in 17% overall yield. Compounds 4a, 4b, 7, 8 and 13 were screened for their ability to inhibit the in vitro rabbit blood platelet aggregation induced by collagen using the Born test. Among the active compounds 4a exhibited an important inhibition at 1 μM concentration.     

Synthesis of 1,2,3,4-tetrahydroquinazoline derivatives as potential alpha-adrenergic blocking agents

The synthesis of N,N′-bis[6-(1,2,3,4-tetrahydro-3-quinazolidyl)hexyl]cystamine (I) and 3-(6-aminohexyl)-1,2,3,4-tetrahydroquinazoline (II) are described. Compound I is obtained by condensation of o-nitrobenzoyl chloride with 3-(6-aminohexyl)-1,3-thiazolidine (III) followed by dimerization, reduction and formation of tetrahydroquinazoline ring. A similar method was used for preparation of compound II. These compounds and some synthesis intermediates are potential alpha-adrenergic blockers.     

Synthesis of new boswellic acid derivatives as potential antiproliferative agents

Abstract

In the current investigation, a series of heterocyclic derivatives of boswellic acids were prepared along with new monomers of 3-O-acetyl-11-keto-β-boswellic acid (AKBA, 1) 11-keto-β-boswellic acid (KBA, 2) and several new bis-AKBA and KBA homodimers and AKBA-KBA heterodimers. The effects of these compounds on the proliferation of different human cancer cell lines, viz., FaDu (pharynx carcinoma), A2780 (ovarian carcinoma), HT29 (colon adenocarcinoma), and A375 (malignant melanoma), have been evaluated. Thus, KBA homodimer 21 effectively inhibited the growth of FaDu, A2780, HT29, and A375 cells with EC₅₀ values below 9?μM. In addition, compounds 7, 8, 11, 12, 15, 16, and 17 also exhibited cytotoxic effects for A2780, HT29, and A375 cancer cells. In particular, the pyrazine analog 8 was highly cytotoxic for A375 cancer cells with an EC₅₀ value of 2.1?μM.     

Synthesis of certain tricyclic quinoline derivatives as potential antiamebal agents

Synthesis of the fused tricyclic systems, 1, 2, 3, 3a, 4, 5-hexahydropyrrolo[1, 2a]quinoline (I) and 2, 3, 4, 4a, 5, 6-hexahydro 1H-benzo[c]quinolizine (II), each bearing an ethoxyl substituent on the benzene ring, has been achieved. The compounds combine certain structural features of the alkaloid emetine and of 8-quinolinols.     

Synthesis of benzimidazole derivatives as potential H1-antihistaminic agents

Several types of benzimidazole derivatives were prepared and were screened for H ₁-antihistaminic activity. Most of the compounds showed potent antihistaminic activity in vitro. Among them 2-[(1-piperazinyl)methyl]-benzimidazoles 14 and 2-[(1-homopiperazinyi)methyl]benzimidazoles 15 exhibited potent activity also in vivo.     

Synthesis and biological evaluation of dihydrotriazine derivatives as potential antibacterial agents

A series of 1,4-dihydro-1,3,5-triazine derivatives were designed and synthesized and their antibacterial and antifungal activities were evaluated. Most of the synthesized compounds showed potent inhibition of several Gram-positive bacterial strains(including multidrug-resistant clinical isolates) and Gramnegative bacterial strains, with minimum inhibitory concentrations(MICs) in the range of 2.1–181.2 mmol/L. Compounds 7a and 7c presented the most potent inhibitory activities against Grampositive bacteria(e.g., Staphylococcus aureus 4220), Gram-negative bacteria(e.g., Escherichia coli 1924),and the fungus Candida albicans 7535, with MICs of 2.1 or 4.1 mmol/L. Especially, compound 7a was the most potent, with an MIC of 2.1 mmol/L against four multidrug-resistant, Gram-positive bacterial strains.The cytotoxic activity of the compound 7a, 7c and 7f was assessed in HepG2 cells, and the results suggest that 1,4-dihydro-1,3,5-triazine derivatives bearing a 6-benzyloxynaphthalen moiety are interesting scaffolds for the development of novel antibacterial agents.     

Design,synthesis and biological evaluation of novel phthalazinone acridine derivatives as dual PARP and Topo inhibitors for potential anticancer agents

In this study,we designed and synthesized a series of phthalazinone acridine derivatives as dual PARP and Topo inhibitors.MTT assays indicated that most of the compounds significantly inhibited multiple cancer cells proliferation.In addition,all the compounds displayed Topo Ⅱ inhibition activity at 10 mol/L,and also possessed good PARP-1 inhibitory activities.Subsequent mechanistic studies showed that compound 9 a induced remarkable apoptosis and caused prominent S cell cycle arrest in HCT116 cells.Our study suggested that 9 a inhibiting Topo and PARP concurrently can be a potential lead compound for cancer therapy.     

Synthesis of several derivatives of methylthiophosphonic acids,cholinesterase inhibitors

Conclusions A series of O,S-dialkylmethyl thiophosphonates were synthesized.Translated from Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya, No. 3, pp. 583–587, March, 1968.     

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 and biological evaluation of novel acenaphthene derivatives as potential antitumor agents

Twelve novel acenaphthene derivatives have been synthesized. The structures of all compounds were confirmed by 1H-NMR, MS and elemental analysis. Their antitumor activities were evaluated in six human solid tumor cell lines, namely non-small cell lung cancer (H460), human colon adenocarcinoma (SW480), human breast cancer cell (MDA-MB-468 and SKRB-3), human melanoma cell (A375) and human pancreatic cancer (BxPC-3). Among them, compound 3c shows the best antitumor activity against SKRB-3 cell line, as high as the positive control adriamycin.     

Exploring the potential of xanthene derivatives as trypanothione reductase inhibitors and chloroquine potentiating agents

Xanthene derivatives were synthesized and evaluated for their potential as trypanothione reductase (TryR) inhibitors and chloroquine (CQ) potentiating agents. Some derivatives displayed inhibitory activity against TryR comparable to known tricyclic anti-depressants. On the other hand a number of derivatives increased CQ accumulation and potentiating effects in a resistant strain of Plasmodium falciparum with one compound also displaying strong intrinsic antimalarial activity.     

Synthesis and biological evaluation of lycorine derivatives as dual inhibitors of human acetylcholinesterase and butyrylcholinesterase

ABSTRACT: BACKGROUND: Alzheimer's disease (AD) is a neurologically degenerative disorder that affects more than 20 million people worldwide. The selective butyrylcholinesterase (BChE) inhibitors and bivalent cholinesterase (ChE) inhibitors represent new treatments for AD. FINDINGS: A series of lycorine derivatives (1--10) were synthesized and evaluated for anti-cholinesterase activity. Result showed that the novel compound 2-O-tert-butyldimethylsilyl-1-O-(methylthio)methyllycorine (7) was a dual inhibitor of human acetylcholinesterase (hAChE) and butyrylcholinesterase (hBChE) with IC50 values of 11.40 [PLUS-MINUS SIGN] 0.66 muM and 4.17 [PLUS-MINUS SIGN] 0.29 muM, respectively. The structure-activity relationships indicated that (i) the 1-O-(methylthio)methyl substituent in lycorine was better than the 1-O-acetyl group for the inhibition of cholinesterase; (ii) the acylated or etherified derivatives of lycorine and lycorin-2-one were more potent against hBChE than hAChE; and (iii) the oxidation of lycorine at C-2 decreases the activity. CONCLUSION: Acylated or etherified derivatives of lycorine are potential dual inhibitors of hBChE and hAChE. Hence, further study on the modification of lycorine for ChE inhibition is necessary.     

Synthesis of dihydrocoumarin carbamate derivatives

The condensation at room temperature in the trifluoroacetic acid of para- and meta-hydroxy-substituted methylphenylcarbamate with cinnamic acids or their esters containing electron-donor substituents in the benzene ring yielded dihydrocoumarins with a carbamate function attached to C⁶ or C⁷. Under similar conditions the methyl(2-hydroxyphenyl)carbamate, cinnamic acids or their esters containing electron-acceptor substituents or electron-donor substituents in the ortho-position of the benzene ring are not involved into the condensation.     

Synthesis of Some amino-4,5-dihydropyrazolo[3,4-a]acridines as potential cholinesterase inhibitors

A synthesis of the 4,5-dihydro derivatives of the previously known pyrazolo[3,4-a]acridine ring system is described. The reaction of a 3,4-dihydroacridin-1(2H)-one with N,N-dimethylformamide dimethyl acetal gave a reactive enamino ketone, which yielded the desired heterocycle upon reaction with hydrazine. Using this chemistry, 11-amino-4,5-dihydro-2H-pyrazolo[3,4-a)acridine ( 3 ) and a number of its 2-substituted derivatives 4a-k were synthesized and evaluated as acetylcholinesterase inhibitors, based on their relationship to 1,2,3,4-tetrahydro-9-acridinamine (THA). 1-Amino-4,5-dihydro-1H-pyrazolo[3,4-a]acridine ( 11a ) and 2-amino-4,5-dihydro-1H-pyrazolo[3,4-a]acridine ( 11b ) were also synthesized and investigated as potential cholinesterase inhibitors.