Studies of Quantitative Structure-Activity Relationship (QSAR) of Hydantoin Based Active Anti-Cancer Drugs

 

Ganatra S. H. ¹, Patle M. R². and Bhagat G. K. ³

¹Institute of Science, Nagpur

²D. B. Sc. College, Gondia

³Jagat Arts Comm. and IHP Sc. College, Goregaon.

*Corresponding Author E-mail: manojpatle14@gmail.com

ABSTRACT:

The paper describes QSAR studies of Hydantoin based compounds as anticancer agents. Present study aimed at finding the equation for Hydantoin based molecules as anticancer agent. On a systematic study, it is possible to enhance the activities of these molecules by using QSAR methodology.

 

 

 

INTRODUCTION:

The premier health organization World Health Organization (WHO) has prepared Global burden diseases report under the instruction of World Bank in the year 1990 to understand the issue of danger level of diseases in developing and under developed countries. According to this report¹, there would be the likelihood of health crisis in the year 2020. Hence it is the urgent need to concentrate research on the most attributable diseases such as Cardio-vascular diseases, Unipolar depression, Cerebrovascular disease, Chronic Lung disease, Lower respiratory track diseases, HIV and Tuberculosis and Cancer².

 

There are the areas, which also needs tremendous research like problems due to road accidents, violence, self- inflicted injuries, etc. This report insists on need to have advanced tools to fight against the challenges due to the above mentioned diseases.¹ Failing will result in pandemonium in the civilized world and will result in the uncontrolled spread of epidemic and violence; hence the society has to reinvent the wheel of progress.²

 

EXPERIMENTAL:

Present study deals with the QSAR study of Hydantoin based series of compounds. The main aim of the experiment is to evaluate Multiple Regression Analysis for the series of newly designed Hydantoin based compounds for understanding the properties of molecules participates in anti-cancer activities.

The stepwise experimental procedure is as follows for both types of molecules.

 

a. Identification of Known Compound Set

In QSAR methodology the first step is the Identification of the Hydantoin based molecule series with known anti-cancer activities from literatures. This set of compounds is treated as Training Set for the design of QSAR model.

The known set of Hydantoin based molecule is procured from the work of Zuping Xia et.al.³ and this set of molecules is treated as Training Set.

 

Table 1 Shows the molecular formula, molecular structure of basic Hydantoin.

Table 1: The basic details of Hydantoin based Molecules.

Common Name	IUPAC Name	Molecular Formula and M.Wt.	Structural Formula
Hydantoin	Imidazolidine-2,4-dione	C3H4N2O2   M.Wt. = 100.08

 

b. Virtual Designed of Known Molecules:

The series of known molecules (which are procured from literature as mentioned above) are designed virtually (in-silico) using the computer based molecule design software CHEMDRAW.^4,5 Both 2D and 3D structures are designed. While designing molecules virtually, precautions are being taken for 3D as it tends to lock in “Local Minima”. Full care is being taken to see that all molecules are reaching to their “Global Minima” and hence the designed molecules are verified for their 3D structures.

 

Total sixteen molecules are designed and verified for their 3D structures. Semi-empirical QM/MM2 method is used to design 3D molecules with ready-made computer based tools. The final structure of the molecule is having very less total energy and having minimum strain.

 

The various physio-chemical properties are derived using the advanced computer model for each known molecules and these properties are listed in table 3 and 4 for Hydantoin (Training Set) and Hydantoin (Test Set ) based molecules respectively.

c. QSAR using stepwise multiple regression analysis

Stepwise multiple regression analysis performed for both series i.e. for Hydantoin based molecule series. Hydantoin based molecule series is named as “Training Set, I”

 

In the preset study, the multiple regression analysis (stepwise) was performed for both the series by treating biological activity as dependent variable and physio-chemical properties as independent variables. The detail methodology and results obtained are described in following section.

 

In this methodology, initially 35 variables (properties) of each molecule are supplied to the system. The properties whose co-efficient has negligible values are removed and again the regression is performed.

 

 

 

Table 2:  Structure, IUPAC Name, molecular formula and Biological Activities of HYDANTOIN based compounds (Training set I.)

Mol. No.	IUPAC Name	Molecular Formula	Mol. WT. (amu)	Biological Activity
1	5,5-diphenyl imidazolidine-2,4-dione	C15H12N2O2	252.274	1.92
2	3-ethyl-5,5-diphenyl Imidazolidine-2,4-dione	C19H16N2O2	280.328	3.76
3	3-butyl-5,5-diphenyl Imidazolidine-2,4-dione	C19H20N2O2	308.382	4.29
4	3-butyl-5,5-bis (4-chlorophenyl) imidazolidine-2,4-dione	C19H18Cl2N2O2	377.272	4.99
5	5,5-bis(4-bromophenyl -3-butylimidazolidine-2,4-dione	C19H18Br2N2O2	466.174	4.71
6	3-pentyl-5,5-diphenyl imidazolidine-2,4-dione	C20H22N2O2	322.409	4.53
7	3-hexyl-5,5-diphenyl imidazolidine-2,4-dione	C21H24N2O2	336.436	5.02
14	3-heptyl-5,5-diphenyl Imidazolidine-2,4-dione	C22H26N2O2	350.463	5.12
15	5,5-bis(4-chlorophenyl) -3-heptylimidazolidine-2,4-dione	C22H24Cl2N2O2	419.352	4.31
16	5,5-bis(4-bromophenyl) -3-heptylimidazolidine-2,4-dione	C22H24Br2N2O2	508.255	4.56
17	3-octyl-5,5-diphenyl Imidazolidine-2,4-dione	C23H28N2O2	364.49	4.87
18	5,5-bis(4-fluorophenyl)-3-octylimidazolidine-2,4-dione	C23H26F2N2O2	400.471	4.89
19	5,5-bis(4-chlorophenyl)-3-octylimidazolidine-2,4-dione	C23H26Cl2N2O2	433.379	3.62
20	5,5-bis(4-bromophenyl)-3-octylimidazolidine-2,4-dione	C23H26Br2N2O2	522.282	3.3
21	3-octyl-5,5-dip-tolyl imidazolidine-2,4-dione	C25H32N2O2	392.544	3.79
22	5,5-bis(4-methoxy phenyl)-3- octylimidazolidine-2,4-dione	C25H32N2O2	424.543	3.52

 

Table 3:  Calculated parameters of Training Set I molecules (Hydantoin based molecules)

Mol. No.	Partition Coefficient	Non-1,4 VDW Energy	Electrical Energy	HOMO	LUMO	Repulsion Energy	Balaben Index	Molecular Topological Index	Wiener index
1	2.085	-4.7877	-20113.1	-9.6191	-0.5775	16976.9	121875	4679	617
2	2.75	-6.283	-24286.8	-9.5557	-0.3734	20838.8	191884	6144	803
3	3.838	-7.6272	-28727.8	-9.497	-0.17247	24968.1	304622	8258	304622
4	5.264	-8.6481	32984.3	-9.65789	-0.47664	28504.7	456592	9642	1371
5	5.564	-8.8531	-32830.2	-9.65725	-0.52357	28391.6	456592	9642	1371
6	4.367	-6.16288	-29338.2	-9.51168	-0.42911	25422.9	382256	9588	1242
7	4.896	-7.7307	-31885.8	-9.5527	-0.36429	27814.6	477641	11084	1435
8	5.425	-6.6512	-32728.9	-9.5048	-0.43832	28507	592640	12784	1653
9	6.851	-6.9399	-36976	-9.64298	-0.69487	32029	838981	14558	2029
10	7.151	-7.04272	-36821.1	-9.6376	-0.71522	31915	838981	14558	2029
11	5.954	-8.2133	-35450.6	-9.55521	-0.35486	31057.8	731174	14686	1897
12	6.24	-8.2287	-40393.8	-9.83808	-0.6979	35069.2	1018686	16610	2303
13	7.38	-8.56599	-39950	-9.60575	-0.64408	34847.5	1018686	16610	2303
14	7.68	-8.68675	-39784.8	-9.68077	-0.67499	34722.9	1018686	16610	2303
15	6.952	-7.04961	-38899.3	-9.26829	-0.26678	34204.9	1018686	17864	2303
16	5.792	-9.44553	-44482.4	-9.40838	-0.32773	39148.2	1402994	20782	2789
17	-99.9	-12.8816	-44482.4	0	0	0	1091347	19128	2467
18	-99.9	-12.394	-44482.4	0	0	0	2253710	30788	3963
19	-99.9	-12.4525	-38215.6	-9.503	-8.27045	33805.5	363669	101552	1313
20	-99.9	-13.4883	-40970.4	-9.51627	-0.46077	36405.1	454729	11804	1525
21	-99.9	-12.0081	-40252.1	-9.50326	-0.45596	35686.3	454724	11804	1525
22	99.9	-11.8299	-41672.3	-9.53381	-0.41771	36950.7	564473	13658	1763

Table 3 (Continue) :  Calculated parameters of Training Set I molecules (Hydantoin based molecules)

Molecule  No.	HF (Kj/ mol)	BP	MP	Tc	Pc	Vc	GE (Kj/ mol)	Log P	Clog P	Henry Law	CMR	MR (cm3\ mol)	B.A. (pI50)	ΔG (Kcal/ mol.)
1	133.92	855.5	666.72	1036	38.82	741.5	376.25	2.14	2.085	14.8	7.2226	69.61	1.92	-9.34694
2	114.01	861.54	694.79	1015.65	30.16	796.5	476.71	2.72	2.78	14.33	8.1502	79.41	3.76	-8.88176
3	72.73	907.3	717.33	1024.52	24.68	908.5	493.55	3.62	3.838	14.09	9.0778	88.61	4.29	-9.79961
4	18.31	992.12	802.21	1056.59	22.31	1006.5	450.43	4.74	5.264	14.35	10.0606	97.82	4.99	-10.4487
5	102.45	1049.58	861.97	1084.52	27.56	1032.5	502.93	5.28	5.564	14.89	10.6318	103.99	4.71	-12.0574
6	52.09	930.18	728.6	1030.23	22.48	964.5	501.97	4.04	4.367	13.96	9.5416	93.21	4.53	-9.96578
7	31.45	953.06	739.87	1039.76	20.57	1020.5	510.39	4.46	4.896	13.84	10.0054	97.81	5.02	-10.3555
8	10.81	975.94	751.14	1044.14	18.89	1076.5	518.81	4.87	5.425	13.72	10.4692	102.41	5.12	-10.8852
9	-43.61	1060.7	836.02	1080.19	17.29	1174.5	475.69	5.99	6.851	13.98	11.452	111.62	4.31	-11.7867
10	40.53	1118.2	895.78	1108.43	20.79	1200.5	528.19	6.53	7.151	14.52	12.0232	117.79	4.56	-11.8436
11	-9.954	998.82	762.41	1052.33	17.4	1132.5	527.23	5.29	5.954	13.59	10.933	107.01	4.87	-10.9039
12	-425.99	1007.3	788.63	1036.74	15.78	1168.5	118.35	5.61	6.24	13.46	10.964	107.82	4.89	-12.4233
13	-64.25	1083.6	847.29	1089.78	15.99	1230.5	484.11	6.41	6.79	13.25	11.9158	116.22	3.62	-10.9013
14	19.89	1141.1	907.05	1118.18	19.09	1256.5	536.61	6.95	7.68	14.39	12.487	122.39	3.3	-11.4088
15	-74.05	1034.3	809.99	1070.72	14.58	1244.5	524.81	6.27	6.952	13.51	11.8606	118.8	3.79	-11.0673
16	-338.49	1099.3	854.45	1094.96	14.21	1280.5	314.81	5.04	5.792	16.05	12.1668	121.5	3.52	-9.8085
17	-51.11	1044.5	784.95	1071.27	14.92	1244.5	544.07	6.13	7.012	13.35	11.8606	116.2	4.31	-10.8852
18	-133.67	1136.1	830.03	1119.75	11.31	1468.5	577.75	7.79	9.128	12.85	13.7158	134.6	3.98	-10.7867
19	85.77	972.61	747.25	1065.57	25	953.5	534.84	3.93	4.192	14.2	9.828	95.62	4.13	-11.8436
20	65.13	995.49	758.52	1070.49	22.76	1009.5	543.26	4.36	4.901	14.07	10.2918	100.31	4.73	-11.9039
21	65.13	995.49	758.52	1070.49	22.76	1009.5	543.26	4.36	4.901	14.07	10.2918	100.31	5	-12.4233
22	44.49	1018.3	769.79	1076.29	20.81	1065.5	551.68	4.71	5.43	13.95	10.7556	104.91	4.3	-9.9013

 

Table 4:  :  Calculated parameters of Test Set I molecules (Hydantoin based designed molecules)

Molecule No.	Partition Coefficient	Non-1,4 VDW Energy	Electrical Energy	HOMO	LUMO	Repulsion Energy	Balaben Index	Mol. Topological Index	Wiener Index	HF (Kj/ mol)	BP	MP	Tc
1	2.124	-8.9351	-40021.3	-8.6517	-0.7367	34883.4	788143	18571	2494	369.54	965.74	966.95	1193.97
2	3.394	-5.861	-27760	-8.5448	-0.3498	24028	245280	7941	1035	44.15	787.63	615.99	1003.16
3	-5.7397	-29373.7	-8.5902	-0.4435	-0.4129	25486.3	307794	9232	1200	23.51	799.24	92.033	1009.75
4	2.254	-7.8207	-22170.1	-9.47241	-8.7564	18948.9	140838	5443	713	-106.24	737.95	520.37	966.663
5	2.813	56.0043	-24975.3	-9.5475	0.1414	21600.7	180070	6329	827	-133.04	750.61	528.12	977.467
6	3.522	-8.7539	-26067.2	-9.5046	-0.1064	22534.2	235608	7557	986	-153.68	762.22	539.39	982.344
7	3.884	-7.9026	-34088	-8.6516	-0.4205	29845.4	478447	13411	1733	203.4	855.57	702.49	1076.45
8	3.709	-7.9528	-32465.4	-8.0453	-9.4155	28350.6	460583	11930	1543	226.82	847.02	738.66	10825.04
9	2.9564	-12.3135	-32465.4	0	0	0	3187367	35286	4927	0	0	0	0
10	2.8368	-11.0932	-61659.2	-8.69351	-0.7315	54950.9	2824085	32711	4591	0	0	0	0
11	3.9828	-8.36417	-62705.6	-8.72814	-0.7705	55772.5	3062920	38026	5285	0	0	0	0
12	3.666	-4.0004	-50439.9	-8.74136	-0.7886	44684.1	1391093	23883	3271	0	0	0	0
13	3.666	-4.0004	-50439.9	-8.74136	-0.7886	44684.1	1391.93	23883	3271	0	0	0	0
14	0.4967	-10.2615	-50439.6	0	0	0	3615430	38151	5321	0	0	0	0
15	4.631	-3.6654	-46100.2	-8.6566	-0.7014	40825.1	1213254	23049	3019	0	0	0	0
16	3.279	-12.8959	-67220.9	-9.25976	-0.36799	59874.9	2471358	30924	4474	0	0	0	0

 

 

Table 4 (Continue)  :  Calculated parameters of Test Set I molecules (Hydantoin based designed molecules)

Molecule No.	Pc	Vc	GE(Kj/mol)	Log P	Clog P	Henry's Law	CMR	MR (cm3\mol)	Cal  B.A.	ΔG kcal/mol
1	26.3796	1077.5	804.06	0	2.124	17.7779	11.288	0	-328.869	-10.7184
2	22.504	881.5	418.68	3.1711	3.394	14.5433	8.9734	87.3557	2.8684	-11.337
3	20.5862	937.5	9.4372	3.5196	3.923	14.4202	3.923	427.1	14653.7454	-11.7528
4	26.7631	739.5	245.89	2.004	2.254	13.1023	7.3168	71.4177	-25.0531	-9.56609
5	24.9003	787.5	242.21	2.4213	2.813	12.9792	7.7806	76.0187	-5.3187	-9.44683
6	22.6757	843.5	250.63	2.8502	3.522	12.8561	8.2444	80.7501	26.29432	-10.5515
7	21.256	1003.5	567.21	3.9604	3.884	15.8824	10.557	102.979	-5.1799	-11.8205
8	24.8259	964.5	634.27	4.0395	3.709	15.5479	10.1976	99.1461	275.5739	-11.9076
9	0	0	0	1.4416	2.9564	30.723	15.0941	148.532	129.3045	-9.24438
10	0	0	0	1.1785	2.8368	33.2284	14.6303	143.763	90.49376	-8.41601
11	0	0	0	1.9589	3.9828	32.7376	15.2167	150.241	136.7852	-13.0292
12	0	0	0	1.5525	3.666	28.3592	13.3365	131.023	113.0631	-9.16567
13	0	0	0	1.5525	3.666	28.3592	13.3365	131.023	134.4775	-8.51007
14	0	0	0	-1.2716	0.4967	7.0487	14.6965	144.454	174.4166	-8.942
15	0	0	0	3.3832	4.631	14.3789	12.9592	127.76	123.2195	-10.3007
16	0	0	0	2.1946	3.279	15.1407	13.8938	142.204	122.0523	-11.7528

 

This method is repeated until all the co-efficient are within the acceptable limits. The detail parameters passed to the model system along with the setting for running the multiple regression analysis. The multiple regression equation is listed in Table 5.

 

The computer based model system provides a number of additional information about the regression including the various plots.

The values of coefficients of various variables and multiple regression equations and listed in Table 5.

 

Table 5: Estimated Model for calculation of biological activity on the basis of regression analysis for Hydantoin based molecule series. (Training Set I ).

Y = -44.7520- 1.4321x10-02xC1+ 2.5051x10-02xC10+ 8.9208 x10-02xC11-8.8081 x 10-02 x C12 + 3.5428x10-02xC13-.3960xC14-.1025xC15-5.9379x10-02xC16-18.1883xC17+ 14.6693 x C18 -1.8915 x C19-.4577xC2-14.2594xC20 + 3.0753xC21-3.7251 x10-06xC3-5.4073xC4 + 5.3735 x C5-1.3837 x10-03xC6-1.5409 x10-05xC7+ 4.7809 x10-04*C8-4.6827 x10-07xC9

Where, C1 - partition coefficient, C2 - non 1,4 VDW energy, C3 - electrical energy,            C4- HOMO, C5 - LUMO, C6 - repulsion energy,          C7 - Balaben index,    C8 - Mol.topological index, C9 - Wiener index,  C10 -HF (kj/mol),   C11 - Boiling Point (BP),  C12 - Melting Point (MP), C13 - critical temperature,  C14 - critical pressure (Pc), C15 - critical volume (Vc), C16-Gibb’s free energy (kj/mol), C17 - Log P, C18 – Clog P, C19- Henry's law constant,            C20 – CMR, C21 - molar refractivity (cm3\mol),                    C22 – Biological Activity, C23 – Binding Energy(ΔG)

The report is generated by computer based statistical analysis software by name NCSS⁶.

 

d. Validation of Model:

It is necessary to test the resulted regression equations. In the present study, the regression equations were tested with the known molecules, which were not included in training set.

It is reported that the experimental biological activity and calculated biological activities of these molecules are nearly matching gives us confidence of our approach.

Table 6 depict the comparison of experimental biological activities with calculated biological activities of known molecules for Hydantoin based molecules respectively.

 

Table 6: Comparison of biological activities of Hydantoin based  known molecules : Experimental and Calculated.

Molecular Formula	IUPAC Name	Experimental Biological Activity (Known B. A..)	Calculated B. A.
C24H32N2O2	5,5-bis(4-hlorophenyl) - 3 - (cyclohexylmethyl) imidazolidine-2,4-ione	5	5
C25H34N2O2	3-(2-cyclohexylethyl)- 5, 5 phenylimidazolidine - 2 , 4 - dione	4.3	4.3

 

e. Design of Hydantoin based “Unknown” molecules:

Once equation for calculating B.A. is known, knowing the needed contributions by any typical properties of molecules, new set of molecules are designed in-silico for both the types.

 

While preparing these molecules care is being taken to see that those properties which enhance the BA are keenly selected in new molecules while those properties which reduce BA are rejected from series.

 

In this table (Table 7) the molecule number provides in unique way. For example, Molecule Number 4a is actually the modification of molecule number 4 from same category of training set. Molecule No. 4 is from the Training Set, whereas Molecule No. 4a is from testing set. (New molecule design by modifying the molecule no. 4) Hence, Molecule No. 4a is a modification (virtually) of a molecule no. 4.

 

 

 

Table 7 :  Structure, IUPAC name and molecular formula of Hydantoin based compounds of Test Set I.

Mol. No.	IUPAC Name	Molecular  Formula	Mol. Wt. (amu)
1a	3-(9H-fluoren-9yl) -5-benzyl imidazolidine- 2,4-dione	C23H15N5O3	409.406
2a	3-(9H-fluoren-9yl)-5-isopropyl imidazolidine- 2,4-dione	C19H18N2O2	306.366
3a	3-(9H-fluoren-9yl) -5-isobutyl imidazolidine- 2,4-dione	C20H20N2O2	320.399
4a	5-benzyl-3- cyclopentyl imidazolidine- 2,4-dione	C15H18N2O2	258.322
5a	5-benzyl-3- cyclohexyl imidazolidine- 2,4-dione	C16H20N2O2	272.349
6a	5-benzyl-3-(cyclohexylmethyl) imidazolidine- 2,4-dione	C17H22N2O2	286.376
7a	5-benzyl-3- (9H-fluoren-9-yl)imidazolidine- 2,4-dione	C23H18N2O2	354.411
8a	3-benzhydryl-5-phenylimidazolidine- 2,4-dione	C12H18N2O2	342.399
9a	2-(2-{3-[3-(1H-imidazol-4-yl)-propyl]-5-methyl-5-naphthalen-1-yl-2,4-dioxo- imidazolidin-1-yl}-acetylamino)-4-methylsulfanyl-butyric acid methyl ester	C28H33N5O5S	551.66
10a	2-(2-{3-[3-(1H-imidazol-4-yl)-propyl]-5-methyl-5-naphthalen-1-yl-2,4-dioxo- imidazolidin-1-yl}-acetylamino)-4-methylsulfanyl-butyric acid,	C27H31N5O5S	537.20
11a	2-(2-{3-[3-(3H-imidazol-4-yl)-propyl]-5-methyl-5-naphthalen-1-yl-2,4-dioxo- imidazolidin-1-yl}-acetylamino)-3-thiophen-2-yl-propionic acid,	C29H29N5O5S	559.64
12a	3-[3-(3H-imidazol-4-yl)-propyl]-5-methyl-5-naphthalen-1-yl-1-(2-oxo-2-thiaz olidin-3-yl-ethyl)-imidazolidin-2,4-dione,	C24H26N5O3S	464.56
13a	3-[3-(3H-imidazol-4-yl)-propyl]-5-methyl-5-naphthalen-1-yl-1-(2-oxo-2-thiaz olidin-3-yl-ethyl)-imidazolidin-2,4-dione,	C25H27N5O3S	477.58
14a	2-(2-{3-[3-(3H-imidazol-4-yl)-propyl]-5-methyl-5-naphthalen-1-yl-2,4-dioxo- imidazolidin-1-yl}-acetylamino)-4-methylsulfonyl-butyric acid,	C27H31N5O7S	569.63
15a	1-benzyl-3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthalen-1-yl-imidazolidin -2,4-dione	C27H26N4O2	438.52
16a	1-(3-trifluoromethyl-benzyl)-3-(3-imidazol-1-yl-propyl)-5-methyl-5-naphthal en-1-yl-imidazolidin-2,4-dione	C29H29F3N4O3	538.56

The modification is done be removing or by adding new functional groups to this molecule. These changes help in either enhancing or reducing the required physio-chemical properties of newly designed molecules. The molecules which show the positive change in the properties are selected. Positive changes means, by changing the functional group the anti-cancer properties of the molecule should enhance and that can be judged by knowing the values of parameters.

 

f. Confirmation of QSAR model and derived equations.

The properties of designed molecules (Test Set I) is utilized to find out the “Calculated Biological Activities” using the equation which is already acquired.

 

RESULTS:

1 Results of Multiple Regression Analysis

Present study envisages the task to find out a best regression analysis for two types of molecular series. They are Hydantoin based molecules. The known series of molecules are already tested for their Biological Activities.

No model is valid until it is checked for the accuracy and reproducibility. In this section, the observed values i.e. the equations for test series ' is used to predict the biological activities of known and unknown set of molecules.

The derived equation for test series I and II is depicted in Table 8

 

Table 8: Derived equation for Test Series I

Equation 1

Y = -44.7520- 1.4321x10-02xC1+ 2.5051x10-02xC10+ 8.9208 x10-02xC11-8.8081 x 10-02 x C12 + 3.5428x10-02xC13-.3960xC14-.1025xC15-5.9379x10-02xC16-18.1883xC17+ 14.6693 x C18 -1.8915 x C19-.4577xC2-14.2594xC20 + 3.0753xC21-3.7251 x10-06xC3-5.4073xC4 + 5.3735 x C5-1.3837 x10-03xC6-1.5409 x10-05xC7+ 4.7809 x10-04*C8-4.6827 x10-07xC9

 

Table 9: Comparison between the experimental BA with calculated BA for training set I

Molecule	B.A.  (pI50)	Calculated B.A.  (pI50)
1	1.92	1.9212
2	3.76	3.7622
3	4.29	4.2932
4	4.99	4.9923
5	4.71	4.7123
6	4.53	4.535
7	5.02	5.012
8	5.12	5.1356
9	4.31	4.367
10	4.56	4.534
11	4.87	4.8567
12	4.89	4.8834
13	3.62	3.645
14	3.3	3.43
15	3.79	3.734
16	3.52	3.525
17	4.31	4.356
18	3.98	3.943
19	4.13	4.158
20	4.73	4.726
21	5	5.012
22	4.3	4.33

 

Using this equation the biological activities for the test series I and II are calculated and it is reported that the values are within 98% confidence level which is the great achievement of present work. Table 9 depicts the comparison between the experimental BA with calculated BA.

 

The calculated BA is in excellent agreement with the desired one and hence the work envisage in present study successfully accomplished.

 

2 Analysis of obtained equation for Hydantoin Molecule

The obtained equation is listed in table 8. On analyzing this equation it is clearly reported that following properties are selected by equation.

 

The values of a coefficient for Training Set ' indicated that Balaben index, Molecular Topological Index, Wiener Index, Repulsion energy, Electrical Energy had the negligible contribution for making Hydantoin based molecules as an anti-cancer agent.

 

Log P, CMR, HOMO, Henry’s Law value contributed negatively in making Hydantoin molecule as an anti-cancer agent. These values reduced the inhibition ability against cancer proteins. From these points, it is recommended to modify the equation as follows.

 

Table 10: Final regression equation for Hydantoin based molecules to predict BA.

Equation 2

Y = -44.7520- 1.4321x10-02xC1+ 2.5051x10-02xC10+ 8.9208 x10-02xC11-8.8081 x 10-02 x C12 +3.5428x10-02xC13-.3960xC14-.1025xC15-5.9379x10-02xC16-18.1883xC17+ 14.6693 x C18 -1.8915 x C19-.4577xC2-14.2594xC20 + 3.0753xC21-5.4073xC4 + 5.3735 x C5

 

CONCLUSION:

The main aim of the Present study was to find out the best regression analysis for two types of molecular series. They are Hydantoin based molecules. It is already known that Hydantoin molecules are the anti-cancer agents but there is a need for the increase in their effectively.

 

QSAR is one of the most acceptable methods to predict the biological activities of series of molecules. For the same the foremost requirement is to have atleast one series of molecules (having same nucleus) whose biological activity in the form of IC50 etc are experimentally known with good accuracy.

The result of QSAR is the equation for the series of molecules whose nucleus is same. Thus by varying the functional groups, the biological activity can be enhanced.

 

From present study, it is concluded that;

Ø  It is possible to find out the predicted biological activities for Hydantoin based molecules.

Ø  The multiple regression analysis reports the various coefficient values for various physio-chemical properties of a molecule. These coefficients help us in rejecting or accepting a particular property for designing a molecule as an anti-cancer agent.

Ø  It is reported that on increasing the chain length, the biological activity increases.

Ø  It is also reported that on increasing the halogen group in a molecule, the biological activity reduces, and it reduces further if the molecule is already having Nitrous Oxide group.

Ø  Hydrophobic nature of a molecule enhances the anti–cancer activities of Hydantoin based molecules.

 

QSAR model has its own limitation. It is a statistical model and the designed molecules are from computer-based software. Furthermore, properties are evaluated using computer-based tools. Though this model does have its certain limitations, but still it helps in finding the better anti-cancer molecules well before synthesizing in the laboratory. Using derived equation, it is now possible to check any Hydantoin based molecule for their anti – cancer activity.

 

It is also possible to know, how one can enhance the activity by substituting the various functional group. In present finding, it is reported to use hydrophobic nature groups to enhance the activity.

 

The derived equation 1 and 2 will help synthetic chemists to design the right molecule before synthesizing it in the laboratory and hence saving number of years and also huge cost. It also helps the environment, as unnecessary chemicals are not wasted. QSAR is also a supportive method for Green Chemistry.

 

REFERENCES:

1.          http://www.who.int/en

2.          King, R.J.B.(2000),Cancer biology, 2^nd Ed, School of biological science university of surrey 158-168.

3.          Zuping Xia, Christian Kinaak, Jian Ma, Zanna M. Beharry, Campbell McInnes, Wenxue Wang, Andrew S. Kraft, and Charles D. Smith J. Med. Chem., 2009, 52(1), 74-86.

4.          CambridgeSoft\ChemOffice2004\ChemDraw\READMECP.HTM

5.          http://sdk.cambridgesoft.com/

6.          www.ncss.com

 

 

Received on 14.07.2011        Modified on 10.08.2011

Accepted on 22.08.2011        © AJRC All right reserved