EHOOPrAHH^ECKAa XHMH3, 2014, moM 40, № 3, c. 379-384
IN VIVO AND IN SILICO PHARMACOLOGICAL STUDIES ON SOME NEW 4-(1,3,4-THIADIAZOL-2-YL)BENZENE-1,3-DIOL ANALOGUES
© 2014 E. Jagie-Mo-Wojtowicz*, A. Niewiadomy**, ***, #, A. Chodkowska*, K. Paw-towski*, K. Sarna**
*Department of Toxicology, Medical University, Chodzki 8, Lublin, 20-093 Poland **Department of Chemistry, University of Life Sciences, Lublin, Akademicka 15, Lublin, 20-950Poland ***Institute of Industrial Organic Chemistry, Annopol 6, Warszawa, 03-236 Poland Recevied November 21, 2013; in final form, December 24, 2013
4-(1,3,4-Thiadiazol-2-yl)benzene-1,3-diols 5-substituted in the heterocyclic ring were obtained by the reaction of the commercially available hydrazides or thiosemicarbazides with sulfinylbis[(2,4-dihydroxyphe-nyl)methanethione]. The synthesized compounds were screened for their influence on CNS in the vivo model. Computer aided prediction tools were used for the evaluation of toxicological properties. Additionally, based on the Lipinski filters, the drug- likeness of compounds was assessed. They revealed that the compounds possess properties which can suggest favorable pharmacokinetics in the body after oral admission.
Keywords: 1,3,4-thiadiazole, influence on CNS, Lipinski's rule, in silico DOI: 10.7868/S0132342314030075
INTRODUCTION
1,3,4-Thiadiazole ring is widely exploited in searching new compounds, with various kinds of biological activities. Many of them were found to possess an extensive spectrum of bioactivity. Particularly 2,5-disubstituted 1,3,4-thiadiazoles are known to exhibit antimicrobial, antitumour, antituberculosis activities [1, 2]. Other compounds act on CNS as anticonvulsant [3], analgesic [4], anti-inflammatory [5, 6], antidepressant and anxiolitic [7] agents.
Some of 1,3,4-thiadiazole derivatives are also applied as classical clinical agents. Acetazolamide (N-5-(aminosulfonyl)-1,3,4-thiadiazol-2-yl)acetamide), the strong inhibitor of several CA isozymes is used to treat glaucoma, epileptic seizures, benign intracranial hypertension, altitude sickness and cystynuria. It is also shown as a potential modulator of anticancer therapies in combination with different cytotoxic agents (alkylat-ing, nucleosides analogues, platinum derivative) [8, 9]. Another one, cefazolin, an antibiotic in the cephalosporin family is mainly used to treat bacterial infections of the skin.
A series of 4-(1,3,4-thiadiazol-2-yl)benzene-1,3-diols exemplified by the general structure in Fig. 1, mainly N-substituted aminoderivatives, had originally
Abbreviations: CA — carbonic anhydrases; CNS — central nervous system; logP — the logarithm of partition coefficient of compound between n-octanol and water; PM3 — parametric method 3; STB — sulfinylbis[(2,4-dihydroxyphenyl)methanethione].
# Corresponding author (e-mail: handuzej.miewiadomy@up.lub-lin.pl).
been synthesized in our laboratory as antifungal and anticancer compounds [10, 11]. They show significant antiproliferative activity against various human cancer cell lines [11, 12]. Simultaneously, in the anticancer concentrations the compounds have no influence on viability of normal cells. Moreover, a prominent neu-roprotective activity of some derivatives was observed in the neuronal cultures exposed to neurotoxic agents like serum deprivation and glutamate [13].
In view of the pharmacological profile of the compounds from 4-(1,3,4-thiadiazol-2-yl)benzene-1,3-diols set (amino- and other derivatives) we considered it interesting to explore further the biological properties of some analogues. In this work the compounds were examined with reference to their effect on the CNS of mice. Additionally selected pharmacokinetic and toxic properties of compounds were predicted by the in silico methods.
RESULTS AND DISCUSSION
4-(1,3,4-Thiadiazol-2-yl)benzene-1,3-diols 5-substi-tuted in the heterocyclic ring were obtained by the reaction of the commercially available hydrazides or thiosemicarbazides with sulfinylbis[(2,4-dihydroxyphe-nyl)methanethione] (STB) in MeOH under reflux (2—3 h) as outlined in Fig. 1. STB as a starting substrate was synthesized from 2,4-dihydroxybenzene-carbiditioic acid and CS2 in diethyl ether. Some analytical data of the compounds under consideration are presented in Table 1.
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JAGIELLO-WOJTOWICZ et al.
O,
R
STB
NH MeOH, À 2-3 h
nh2
ho-
OH
W /
(I), (I), (V)
Kjf
R
(I):
R =
HO Me
-Ö
HO.
(II): Il
R.
OH
STB
S
N N H H
-NH2 MeOHfÀ 3 h HO-ri-^
Y
NH—R
STB: HO.
N' (III), (IV)
OH
OH S S OH
(V):
(III):
(IV):
Cl
Scheme 1. Scheme of synthesis and chemical structures of compounds (I)—(V).
The results of the preliminary pharmacological (IV) and (V) weakly affected the CNS of mice. In all
studies including the influence of the compounds on tests compound (II) possessing the 2-hydroxynaph-
the CNS of mice are presented in Table 2. The results thyl substituent was inactive. However, this effect can-
show that only four investigated compounds (I), (III), not be associated with a degree oflipophilicity of com-
S
Table 1. Analytical data of 4-(1,3,4-thiadiazol-2-yl)benzene-1,3-diolsa
No. m.p. [°C] IR ( v, cm-1) H NMR (,ppm) EI MS (m/z, B)
(I) 271- 273 3344 (OH), 1629 (C=N), 1596 (C=C), 1527, 1243 (C-OH), 681 (C-S-C) 11.34 (1 H, s, 3CAr), 11.24 (1 H, s, 2'CAr), 10.13 (1 H, s, 1CAr), 2.28 (3 H, s, CH3) 300 (M+, 100), 271 (8), 167 (18), 165 (13), 153 (8), 151 (5), 150 (4), 132 (22), 77 (9), 39 (7)
(II) 260- -261 3394 (OH), 3056, 3055 (CAR-H), 1631 (C=N), 1600 (C=C), 1521, 1218 (C-OH), 685 (C-S-C) 11.30 (1 H, s, 3CAr), 11.16 (1 H, s, 3'CAr), 10.11 (1 H, s, 1CAr) 336 (M+, 100), 308 (11), 168 (12), 167 (11), 153 (5), 140 (12), 135 (3), 114(12)
(III) 265- 266 3245, (OH, NH), 3055 (CAR-H), 1626 (C=N), 1598 (C=C), 1225 (C-OH), 1110 (C-Cl), 677 (C-S-C) 11.02-9.80 (3 H, broad band, 1 and 3CAr, NH) 319 (M+, 100), 184 (36), 167 (5), 152 (5), 153 (10), 149 (16), 136 (8), 121 (5), 111 (6), 94 (10)
(IV) 230- -231 3191 (OH, NH), 1618 (C=N), 1575 (C=C), 1515, 1220 (C-OH), 673 (C-S-C) 11.10 (1 H, broad band, 3CAr), 10.26 (1 H, s, 1CAr), 10.03 (1 H, s, NH), 3.27 (2 H, s, CH2) 299 (M+, 100), 298 (12), 165 (5), 164 (37), 153 (11), 150 (13), 135 (11), 131 (13), 121 (7), 106 (10), 94 (19), 91 (15)
(V) 216- 218 3418 (OH), 3082 (CAR-H), 2925 (CH2), 1634 (C=N), 1600 (C=C), 1527, 1219 (C-OH) 1106 (C-Cl), 679 (C-S-C) 11.08 (1 H, s, 3CAr), 10.05 (1 H, s, 1CAr), 5.70 (2 H, s, CH2) 369 (M+, 2), 368 (11), 333 (4), 209 (5), 208 (12), 207 (100), 178 (2), 167 (4), 154 (4), 153 (47)
a Detailed data of some compounds were presented previously [11].
IN VIVO AND IN SILICO PHARMACOLOGICAL STUDIES ON SOME NEW
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Table 2. Antinociceptive activity of compounds (I)—(V) in the writhing syndrome test in mice (N = 8)
Compound Treatment mg/kg i.p. Mean writhing number Inhibition3
Control (I) — 25.5 ± 5.0 -
5.0 22.4 ± 6.8 12.1
10.0 12.5 ± 3.7* 50.9*
20.0 4.7 ± 1.8** 81.5**
Control (II) - 22.0 ± 4.9 -
100.0 16.9 ± 6.1 23.18
Control (III) - 26.5 ± 5.3 -
25.0 15.4 ± 4.9 41.8
50.0 4.0 ± 2.8** 84.9**
100.0 3.2 ± 1.8** 87.9**
Control (IV) - 22.0 ± 4.9 -
50.0 15.4 ± 4.7 30.0
100.0 1.0 ± 0.9** 95.45**
Control (V) - 25.5 ± 5.0 -
25.0 27.6 ± 6.9 8.23
50.0 2.2 ± 1.8* 91.3**
100.0 5.3 ± 2.4** 79.2**
Compounds were administered 30 min before the test. a % of inhibition obtained by comparison with the control group. * p < 0.005 vs the control group. **p < 0.001 vs the control group.
pound as analogue (II) possesses the average value of lipophilicity compared to others (Table 3).
None of the compounds exhibited the neurotoxic properties because they did not affect the motor coordination of mice in the chimney test. Moreover, none of the compounds influenced the body temperature and thiopental-induced sleep time in animals.
Four compounds (I), (III), (IV) and (V) displayed antinociceptive activities in the writhing syndrome test (Table 2). Compounds (I), with 2-hydroxy-3-methyl-phenyl substituent, (III), with 3-chlorophenylamine
substituent, and (V) with 2,4-dichlorophenoxymethyl moiety were more active than benzyl derivative (IV). Derivatives (I), (III) and (V) in the doses of100 and 50 mg/kg significantly decreased the number of writhing episodes induced by 0.6% acetic acid in mice. Only the dose of 100 mg/kg of compound (IV) displayed anti-nociceptive activity.
In the remaining tests in question none of the compounds exerted a statistically significant effect.
To estimate the pharmacokinetic properties of the compounds under consideration their some physico-chemical properties were determined (Table 3). The results show that the obtained analogues obey the Lipins-ki's rule of five [14]. Their molecular weight is <500 Da and the octanol-water partition coefficient expressed as Clog P is <5. The compounds possess not more than 5 atoms being an H-bond donor and not more than 10 atoms being an H-bond acceptor. It means that there is high probability that the compounds can have favorable pharmacokinetics after the oral admission.
For the evaluation of toxicological properties of compounds the modular framework lazar (lazy structure—activity relationships) for predictive toxicology was applied. It uses data mining algorithms to derive predictions for untested molecule from experimental training data. Any dataset with chemical structures and biological activities can be used as training data [15]. The carcinogenic and mutagenic potency of compounds in different models is presented in Table 4. The results show that the compounds under consideration are relatively safe. The predictions indicate that the compound with 2-hydroxy-3-methylphenyl substituent (I) is the most promising. However, the predictions for derivative (III) with 3-chlorophenylamine substituent were the worst. On the other hand the low acute toxicity LC50 (EPA v4b fathead minnow model) for this derivative was found in the analyzed group of compounds (Table 4).
Comparable to the test compounds, t
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