In Silico Prediction of Anticonvulsant Activity of

N-(2,2,2-Trichloro-1-hydroxyethyl)alkenyl- and –alkylarylcarboxamides

 

Pavlo V. Zadorozhnii*, Nina P. Popykhach, Vadym V. Kiselev, Ihor O. Pokotylo, Oxana V. Okhtina, Aleksandr V. Kharchenko

 

ABSTRACT:

In this paper, we have predicted the spectrum of the biological activity of N-(2,2,2-trichloro-1-hydroxyethyl)alkenyl- and -alkylarylcarboxamides using the PASS system, as well as their prospects as potential anticonvulsants. The probability of anticonvulsant activity has been shown to be considerably higher for -alkylarylcarboxamides than for -alkenylcarboxamides. For the structures analyzed, an acute toxicity assessment has been carried out in rats using the GUSAR program. We have selected the compounds leaders with the probability of anticonvulsant activity of more than 80%. The structures of the compounds leaders have been tested for compliance with Lipinski criteria.

 

 

INTRODUCTION:

Epilepsy is a chronic disorder associated with abnormal electrical activity in the brain, which is characterized by recurrent, unprovoked seizures¹. The search for new antiepileptic drugs is a very important and urgent task, which, on the one hand, is related to the practical needs of pharmacy and medicine, and on the other hand, allows a more detailed study of the biochemical and biophysical processes occurring in the brain^2-6.

 

This article is a continuation of our series of studies on the search for potential antiepileptic drugs among N-(2,2,2-trichloro-1-hydroxyethyl)carboxamides⁷. At this stage of the research, the sample is taken from SciFinder library of structures using modern QSAR methods⁸. The prediction of anticonvulsant activity of N-(2,2,2-trichloro-1-hydroxyethyl)carboxamides is carried out using the PASS system⁹, whereas an acute toxicity estimate in rats is carried out using the GUSAR program¹⁰. The selected compounds leaders are tested for compliance with Lipinski criteria¹¹.

 

MATERIAL AND METHODS:

The spectrum of biological activity is the whole complex of biological effects that a substance is able to induce under certain conditions of interaction with biological objects              taking into account the peculiarities of specific experiments. It is this concept that the principle of operation of the computer system PASS is based on (Prediction of Activity Spectra for Substances)¹². It predicts the spectrum of biological activity of organic compounds based on their structural formulas, i.e. biological activity of a substance is considered as its internal property depending only on its structure⁹.

 

The PASS system provides an estimate of "similarity / difference" of a testing compound towards the known biologically active substances. The results of prediction are presented as a list of possible types of activity with calculated estimates of the presence (P_a) and absence (P_i) having a value between 0 and 1. The higher the value (P_a) and the lower (P_i) for the specific activity, the greater is the probability of detection of this activity under the experimental conditions⁹.

 

Using the PASS system we have analyzed the spectrum of biological activity of N-(2,2,2-trichloro-1-hydroxyethyl)alkenyl- and -alkylarylcarboxamides. The prediction has been prepared for individual structures, taken from the international database SciFinder (https://scifinder.cas.org). We have introduced the structures of compounds for biological activity prediction using the graphical editor Marvin Sketch at the official website (http://www.pharmaexpert.ru). Then, these structures have been sent to the server as MNA-descriptors (Multilevel Neighborhoods of Atoms)^9,12. The results of the prediction of biological activity spectrum have been visualized on the display and saved by "copy-paste".

 

RESULTS AND DISCUSSION:

Depending on the nature of the substituent of the amide fragment, all the compounds analyzed were divided into 2 groups: 1) alkenyl and 2) alkylaryl (Fig. 1). The probability of anticonvulsant activity of the testing compounds is 39.9% -86.9% (see Table 1-2).

 

 

Fig. 1: General view of

N-(2,2,2-trichloro-1-hydroxyethyl)carbox-amides.

 

 

Table 1: The results of prediction of anticonvulsant activity and acute toxicity of N-(2,2,2-trichloro-1-hydroxyethyl)alkenylcarboxamides.

Compound	R	CAS Number	Anticonvulsant activity		Toxic, LD50 mg/kg
			Pa	Pi	IV	Oral.
1.1		16328-30-6	0.652	0.013	52.950	1460.000
1.2		14825-93-5	0.637	0.014	41.780	1394.000
1.3		13855-75-9	0.585	0.021	50.280	1652.000
1.4		863036-54-8	0.641	0.014	62.170	1922.000
1.5		118641-32-0	0.570	0.023	132.500	2072.000
1.6		902268-09-1	0.456	0.046	90.360	247.800
1.7		863036-55-9	0.690	0.010	87.140	1086.000
1.8		863036-53-7	0.642	0.014	76.590	2557.000
1.9		898472-67-8	0.631	0.015	51.000	2737.000
1.10		863036-63-9	0.616	0.017	77.790	1744.000
1.11		51249-46-8	0.616	0.017	77.790	1744.000
1.12		863036-56-0	0.747	0.008	80.130	3425.000
1.13		863036-60-6	0.667	0.012	119.300	3364.000
1.14		863036-62-8	0.536	0.028	170.600	1167.000
1.15		863036-57-1	0.502	0.035	107.500	1075.000
1.16		863036-61-7	0.580	0.022	48.850	3119.000
1.17		56737-15-6	0.558	0.025	58.340	1201.000
1.18		863036-64-0	0.399	0.065	187.600	1770.000
1.19		863036-63-9	0.433	0.052	136.700	1364.000
1.20		475045-74-0	0.608	0.018	44.040	1256.000
1.21		1322257-68-0	0.608	0.018	44.040	1256.000

 

Table 2: The results of prediction of anticonvulsant activity and acute toxicity of N-(2,2,2-trichloro-1-hydroxyethyl) alkylarylcarboxamides.

Compound	R	CAS Number	Anticonvulsant activity		Toxic, LD50 mg/kg
			Pa	Pi	IV	Oral.
2.1		56737-19-0	0.769	0.007	117.600	1841.000
2.2		726-20-5	0.762	0.007	142.100	914.700
2.3		90842-52-7	0.814	0.005	159.500	498.500
2.4		98946-72-6	0.790	0.005	156.800	1337.000
2.5		99184-27-7	0.620	0.017	680.800	1695.000
2.6		5961-23-9	0.750	0.008	128.200	1743.000
2.7		1017522-73-4	0.663	0.012	56.380	2493.000
2.8		1179480-23-9	0.626	0.028	333.200	1488.000
2.9		102541-39-9	0.740	0.008	187.300	1365.000
2.10		924637-59-2	0.623	0.016	69.470	2143.000
2.11		351004-16-5	0.594	0.020	126.400	4709.000
2.12		24131-09-7	0.752	0.007	49.840	2357.000
2.13		105789-04-6	0.576	0.023	144.100	982.700
2.14		323591-85-1	0.678	0.011	96.560	2896.000
2.15		861053-13-6	0.869	0.004	91.520	2719.000

 

The probability of anticonvulsant activity is significantly higher for N-(2,2,2-trichloro-1-hydroxyethyl)alkylaryl carboxamides than for N-(2,2,2-trichloro-1-hydroxyethyl)alkenylcarboxamides (Table 1, 2, Fig. 2). For –alkylarylcarboxamides the calculated LD₅₀ value for the intravenous route of administration is higher than for -alkenylcarboxamides, that is, the toxicity of -alkyl aryl carboxamides is lower (Fig. 3). A similar dependence is also observed for the toxicity in the oral route of administration (Fig. 4).

 

Fig. 2: Probability of anticonvulsant activity of N-(2,2,2-trichloro-1-hydroxyethyl)alkenyl- (black) and -alkylarylcarboxamides (red).

 

Fig. 3: The estimated LD₅₀ value in intravenous administration of N-(2,2,2-trichloro-1-hydroxyethyl)alkenyl- (black) and -alkylarylcarboxamides (red).

 

 

Fig. 4. The estimated LD₅₀ value in oral administration of N-(2,2,2-trichloro-1-hydroxyethyl)alkenyl- (black) and -alkylarylcarboxamides (red).

Compounds leaders were assigned to the structures having the probability of anticonvulsant activity more than 80%. Of all the compounds studied, two structures (2.3) and (2.15) will have the greatest probability of anticonvulsant activity. The compounds leaders were tested for compliance with Lipinski criteria using the Molinspiration web resource (http://www.molinspiration.com/cgi-bin/properties). All the compounds meet the criteria (Table 3).

 

Table 3: The test of the compounds leaders for compliance with Lipinski criteria

Entry	Compound	Mr	logP	Rot.Bond	Hdonor	Hacceptor
1	2.3	317.00	3.09	4	2	3
2	2.15	324.63	3.83	6	2	3

 

CONCLUSION:

In this paper, using the PASS system, we have predicted the spectrum of the biological activity of N-(2,2,2-trichloro-1-hydroxyethyl)alkenyl- and                                      -alkylarylcarboxamides. They are shown to be potential anticonvulsants. It is shown that for                                           -alkylarylcarboxamides the probability of anticonvulsant activity is significantly higher than for                                      -alkenylcarboxamides. Acute toxicity in rats has been evaluated for the structures analyzed with the use of the GUSAR program. We have selected the compounds leaders, which have the probability of anticonvulsant activity more than 80%. The structures of the compounds leaders have been tested for compliance with Lipinski criteria.

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

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Accepted on 01.11.2017        © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(2):711-716.