научная статья по теме ACETYLCHOLINESTERASE INHIBITION ACTIVITY OF SOME QUINOLINYL SUBSTITUTED TRIAZOLOTHIADIAZOLE DERIVATIVES Химия

Текст научной статьи на тему «ACETYLCHOLINESTERASE INHIBITION ACTIVITY OF SOME QUINOLINYL SUBSTITUTED TRIAZOLOTHIADIAZOLE DERIVATIVES»

ACETYLCHOLINESTERASE INHIBITION ACTIVITY OF SOME QUINOLINYL SUBSTITUTED TRIAZOLOTHIADIAZOLE DERIVATIVES

© 2015 Muhammad Rafiq", Qamar Abbas", Muhammad Saleem4, Muhammad Hanifc,

Ki Hwan Lee4, and Sung-Yum Seo", 1

aDepartment of Biology, Kongju National University, Kongju, 314-701 Korea bDepartmentof Chemistry, Kongju National University, Kongju, 314-701 Korea cDepartment of Chemistry, Quaid-i-Azam University, Islamabad, 45320 Pakistan Received May 12, 2014; in final form 28.08.2014

A series of aralkanoic acids was converted into aralkanoic acid hydrazides through their esters formation. The aralkanoic acid hydrazides upon treatment with carbon disulfide and methanolic potassium hydroxide yielded potassium dithiocarbazinate salts, which on refluxing with aqueous hydrazine hydrate yielded 5-aralkyl-4-amino-3-mercapto-1,2,4-triazoles. The target compounds, 3-aralkyl-6-(substitutedquinolinyl)[1,2,4]tri-azolo[3,4-b][1,3,4]thiadiazoles, were synthesized by condensing various quinolinyl substituted carboxylic acids with 5-aralkyl-4-amino-3-mercapto-1,2,4-triazoles in phosphorus oxychloride. The structures of the newly synthesized triazolothiadiazoles were characterized by IR, 1H NMR, 13C NMR, and elemental analysis studies. The structure of one of the 5-aralkyl-4-amino-3-mercapto-1,2,4-triazoles was unambiguously deduced by single crystal X-ray diffraction analysis. All the synthesized compounds were screened for their acetylcholinesterase inhibition activities. Four of the triazolothiadiazoles exhibited excellent acetylcholinest-erase inhibition activities as compared to the reference inhibitor.

Keywords: quinolinyl substituted triazolothiadiazole, X-ray diffraction analysis, acetylcholinesterase inhibition assay.

DOI: 10.7868/S0132342315020086

INTRODUCTION

Acetylcholinesterase is a serine hydrolase (AChE, acetylcholine hydrolase, EC 3.1.1.7) that plays an essential role in the cholinergic synapses. Hydrolysis of the neurotransmitter acetylcholine in the nervous system by acetylcholinesterase is known to be one of the most efficient enzyme catalytic reactions [1]. The basis of this high efficiency has been sought by means of ligand-binding studies using various substrates and has led to the suggestion that the active center is composed of a cationic esteratic subsite containing the active serine, an anionic site, which accommodates the choline moiety of acetylcholine, and a peripheral anionic site (PAS) [2]. The primary physiologic that the active center is composed of a cationic esteratic subsite containing the active serine, an anionic site, which accommodates the choline moiety of acetylcholine, and a peripheral anionic site (PAS) [2]. The primary physiologic role of the acetylcholinesterase peripheral site is to accelerate the hydrolysis of acetylcholine at low substrate concentrations [3, 4].

The role of cholinergic system has been an intensive issue of interest in Alzheimer disease, which is a

1 Corresponding author (e-mail: dnalove@kongju.ac.kr).

neurodegenerative disorder causing deterioration of memory and other cognitive functions [5, 6]. In Alzheimer's disease, a cholinergic deficiency in the brain has been reported [7]. Therefore, the synthesis and study of inhibitors of acetylcholinesterase may aid to the development of therapeutically useful compounds to treat such neurological disorders. Acetylcholinesterase inhibitors donepezil hydrochloride, galantamine hydrobromide, and rivastigmine tartrate are the current approved drugs for the treatment of Alzheimer's patients [8]. However, acetylcholinest-erase inhibitors present some limitations, such as their short half-lives and excessive side effects caused by activation of peripheral cholinergic systems, as well as hepatotoxicity, which is the most frequent and important side effects of these drug therapies [9—11]. For this reason, alternative and complementary therapies need to be developed. The present work includes the synthesis of new series of biheterocycles containing triaz-ole and thiadiazole ring coupled with substituted quinolinyl carboxylic acids that show good acetylcho-linesterase inhibition activity.

RESULTS AND DISCUSSION

Synthetic pathway adopted for the synthesis of 5-aralkyl-4-amino-3-mercapto-1,2,4-triazoles (\&—h) and 3-aralkyl-6-(substitutedquinolinyl)[1,2,4]triazo-lo[3,4-&][1,3,4]thiadiazoles (Via—v) is illustrated in Scheme. Briefly, substituted aralkanoic esters (IIa—h) were synthesized by the reaction of corresponding substituted aralkanoic acid (Ia—h) in the presence of catalytic amount of sulfuric acid. The synthesized esters (IIa—h) were converted into corresponding aralkanoic acid hydrazides (IIIa—h) by refluxing with hydrazine hydrate (80%) in methanol; the reaction of hydrazides with carbondisulfide in methanolic potassium hydroxide at low temperature yielded an intermediate, potassium dithiocarbazinate (IVa—h), which on reflux with aqueous hydrazine gave 5-aralkyl-4-amino-3-mercapto-1,2,4-triazoles (Va—h). Structures of 5-aralkyl-4-amino-3-mercapto-1,2,4-triazoles (Va—h) were confirmed by IR and NMR spectroscopy. The tautomeric structureof one of the triazoles (Vf) was determined using single crystal X-ray diffraction

analysis. Condensation of the 5-aralkyl-4-amino-3-mercapto-1,2,4-triazoles (Va—h) with quinolinyl substituted carboxylic acids in phosphorus oxychloride resulted in the synthesis of target compounds, 3-aralkyl-6-(substitutedquinolinyl)[1,2,4]triazolo[3,4-è][1,3,4]thiadiazoles (Via—v). Formation of triazo-lothiadiazoles (Via—v) was deduced from the IR spectral data by the disappearance of signals typical to NH absorption for the primary and secondary NH group attached to triazole moiety. In the 1H NMR spectra, the disappearance of singlet peaks for NH and NH2 protons of 5-aralkyl-4-amino-3-mercapto-1,2,4-tria-zoles (Va—h) confirms the ring closure of thiadiazole. Condensation of quinolinyl carboxylic acids with 5-aralkyl-4-amino-3-mercapto- 1,2,4-triazoles (Va—h) was further confirmed by increased number of signals in the aromatic region in both 1H NMR and 13C NMR spectra of 3-aralkyl-6-(substitutedquinolinyl)-[1,2,4]triazolo[3,4-è] [ 1,3,4]thiadiazoles (VIa-v). Experimental values of elemental analysis were in good aggrement with the calculated ones.

OH

X

NH2 iii

(Ia—h)

O X

( IIa—h)

X

X

( IIIa-h)

N

H

(IVa-h)

S K

I-Va, X = 4-Br

b, X = 3-Br

c, X = 4-OCH

d, X = 3-OCH

e, X = 2-OCH3

f, X = 2-F

g, X = 3-F

h, X = 4-OCH3

n = n = 1

n = 1 n = 1 n = 1 n = 1 n = 1 n = 2

X-

N-N

N S

X

nh2

I z

N >=S

nnh

(VIa-v)

(Va-h)

VIa, X = 4-Br

b, X = 3-Br

c, X = 4-OCH

d, X = 3-OCH

e, X = 2-OCH3

f, X = 2-F

g, X = 3-F

h, X = 4-OCH

i, X = 4-Br j, X = 2-F k, X = 3-F

Y =

Y =

Y =

Y =

Y =

Y =

Y =

Y =

Y =

Y =

Y =

2-Quinolinyl 2-Quinolinyl 2-Quinolinyl 2-Quinolinyl 2-Quinolinyl 2-Quinolinyl

2-Quinolinyl

3-Quinolinyl 3-Quinolinyl 3-Quinolinyl 3-Quinolinyl

n n n n n n n n n n n

3

3

l, X = 3-OCH3 m, X = 2-OCH n, X = 2-F o, X = 4-OCH p, X = 4-Br q, X = 2-F r, X = 4-OCH3 s, X = 4-Br t, X = 2-F u, X = 4-OCH3 v, X = 4-Br

Y = 3

Y = 3

Y = 4

Y = 4

Y = 4

Y = 5-

Y = 5

Y = 5

Y = 6

Y = 6

Y = 6

Quinolinyl n

Quinolinyl n

Quinolinyl n

Quinolinyl n

Quinolinyl n

Quinolinyl n

Quinolinyl n

Quinolinyl n

Quinolinyl n

Quinolinyl n

Quinolinyl n

Scheme. Synthesis of 3-aralkyl-6-(substitutedquinolinyl)[1,2,4]triazolo[3,4-£][1,3,4]thiadiazoles (VIa—v). Reagents and conditions: (i) H2SO4(conc.), methanol, reflux, 8-10 h; (ii) Hydrazine hydrate (80%), methanol, reflux, 10-12 h; (iii) CS2, KOH, methanol, stirring, 0°C, 1 h; (iv) Hydrazine hydrate (80%), methanol, reflux, 10-12 h; (v) POCl3,substituted quinolinyl carboxylic acid, reflux, 4-6 h.

1

V

Crystal Structure Determination of Compound (Vf)

For the disubstituted 1,2,4-triazoles, two tautomeric forms (i.e., 4,5-disubstituted-4#-1,2,4-triaz-ole-3-thiol (a) and 3,4-disubstituted-1#-1,2,4-triaz-ole-5(4#)-thione (b)) are theoretically possible because the labile hydrogen can be attached to the nitrogen or sulfer atom, as shown in the thiol—thione tautomeric forms below. In order to investigate the major contributing structure, we have selected compound (Vf) for single crystal XRD-analysis. The results indicated that triazole derivative predominantly existed in thione conformation as shown in (Fig. 1).

N1

N2-

R

n-n

(a)

Scheme.

R

Y

N-N

H

(b)

F1 C5 C„6/

C4 Sñ C2

S1

Fig. 1. The molecular structure of one of the triazole molecules (Vf) with the atom-numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.

Crystal data. C9H9FN4S, Mw = 224.26, triclinic, space group P-1, a = 6.54460(10), b = 6.74380(10), c = 11.0531(2) Á, a = 96.6600(10), p = 100.2400(10), Y = 96.1280(10)°, V = 472.758(13) Á3 at 100 K, Z = 2, Dx = 1.575 Mg/m3, | = 0.326 mm-1, F (000) = 232.

Acetylcholinesterase Inhibition Activity

All the synthesized triazolothiadiazoles (VIa-v) were evaluated for acetylcholinesterase inhibition activity. Neostigmine methyl sulfate with IC50 value of 2.42 ± 0.01 |M was used as a reference inhibitor. Almost all compounds exhibit moderate to excellent activities as compared to the reference inhibitor. Compound (VIi) with IC50 value of 0.89 ± 0.03 |M showed maximum acetylcholinesterase inhibition activity among the whole synthesized series. It has 4-bro-mobenzyl group as substituent X and 3-quinolinyl group as substitent Y. Compounds (VIk) and (VIs) with IC50 values of 1.13 ± 0.08 and 2.08 ± 0.03 |M showed excellent inhibition exceeding that of the standard inhibitor. Compound (VIn) with IC50 values of 2.89 ± 0.06 showed comparable activity to the reference inhibitor. These compounds possesed 3-fluo-robenzyl, 2-fluorobenzyl, and 4-bromobenzyl groups as substituent X and 3-quinolinyl, 5-quinolinyl, and 4-quinolinyl groups as substituent Y, respectively. Compound (VIv) with 4-bromo group as substitent X and 6-quinolinyl group as substitent Y with IC50 values of 96.46 ± 4.12 |M showed minimum ace

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