Study Of 2,3- Diaryl Cyclopentenones As Selective Cyclooxygenase –2 Inhibiters By 3-D QSAR Analysis

A Quantitative Structure Activity Relationship (QSAR) study of the 2,3-diaryl cyclopentenones was made using APEX 3-D INSIGHT II Software. The various biophoric and secondary sites were identified and used for deriving QSAR equations. Several statistical regression expressions were obtained during multiple linear regression analysis. The best QSAR model was further validated by Leave One Out cross validation method. The parameters like refractivity, hydrophobicity, hydrogen bonding site etc were found to be significant.

Key words : 3D-QSAR, Diaryl Cyclopentenones, Selective Cyclooxygenase –2 Inhibiters

INTRODUCTION

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used drugs in the treatment of various disorders caused due to inflammation like arthritis^1,3, Osteo-arthritis, gout, rheumatic fever, systemic lupus erythematus, psoriasis and polyarthritis nodosa.

Wide variety of inflammatory mediators produced from arachidonic acid like prostaglandin’s, thromboxanes are responsible for the inflammatory reactions. Cyclo-oxygenase enzyme (COX-1 and COX-2)² takes part in conversion of arachidonic acid to prostaglandin’s, and thromboxanes. Most of NSAID’s in current use are inhibitors of COX-1 and COX-2 isoenzymes, though they vary in degree of inhibition of each. Anti-inflammatory actions of NSAID’s are related to inhibition of COX-2 and their unwanted effects are due largely to their inhibition of COX-1. The newer drugs, which are selective inhibitors of COX-2, are therefore preferred in the treatment^{4, 5}.

The aim of present study is to correlate and exploit various parameters with Pharmacological activity by QSAR^{6, 7,8} study.

The present study is performed by using APEX-3D, INSIGHT-II software at CDRI, Lucknow.

{mospagebreak title=Materials and Methods}

MATERIALS AND METHODS

A reported series of 2,3-Diaryl Cyclopentenones⁹, as orally active selective COX-2 inhibitor was taken for analysis (Table I).

ØThe biological activity of compounds in series is of in vitro analysis.

ØCompounds in the series have wide range of biological activity.

ØCompounds in the series have minimum number of substituents on basic nucleus.

The basic nucleus of selected series

The molecular modeling studies were performed using APEX 3-D INSIGHT-II Software (Biosym Technologies, San Diego)¹⁰.

The energy calculations were done by CFF force field. All the structures were energy minimized by standard minimizing alogarithm.

The biological activity IC₅₀mM was converted to -LogIC₅₀ for QSAR^11,12,13 analysis with following parameters.

1) Biophore Site: Pi-popul, Charge, HOMO, LUMO, DON-1, ACC-1, Hydrophobicity, Refractivity.

2) Secondary Sites: H-acceptor – Presence, H-Donor- Presence, Hetero atom – Presence, Hydrophobicity- Hydrophobic, Stearic- Refractivity, Ring- Presence.

3) Other setup : Site radius-1.20, Occupancy –7, Sensitivity-1.00, Randomisation- 100

To perform QSAR analysis stepwise multiple regression analysis^14-15 with leave one out method was used. The statistical parameters were considered to compare the generated QSAR models were 1) Co-efficient of correlation (r) 2) Standard deviation (S) 3) F-test, 4) Root Mean Square Activity Approximation (RMSA) 5) Root Mean Square Prediction (RMSP)¹⁶.

The descriptors used for present study are indicated in Table II.

{mospagebreak title=Results and Discussion}

RESULTS AND DISCUSSION

The series has two different sets namely Internal Test Set and Training Sets. Internal test set compounds were selected having highest and lowest biological activity (Table III) and remaining compounds were kept in training set. When the compounds were subjected to QSAR analysis different 21 models were obtained (Table IV). Depending upon RMSA and RMSP difference, Correlation co-efficient, Size, Match, Number of Variables and Number of compounds, five models namely A,J,Q,R and U were selected and experimental activity of test set compounds was compared with predicted activity (Table V). Statistically models Q and R were found most appropriate as they shown maximum correlation between experimental and predicted activities. The figure 1 and 2 shows the Experimental Vs Predicted activity and Experimental Vs Calculated activity of Model Q respectively. The figure 3 and 4 shows the Experimental Vs Predicted activity and Experimental Vs Calculated activity of Model R respectively.

To generate 3-D QSAR equation for above models –logIC₅₀ mM as dependent variable and secondary sites such as H-acceptor presence, H-donor presence, Heteroatoms presence, Hydrophobic - Hydrophobicity, Stearic- refractivity and Ring presence were used as independent variables.

The Equations of Two Selected Models having Significant Activity

Model – R

This model considers two variables namely total Hydrophobicity and refractivity for generation of QSAR equation. Total Hydrophobicity is a global property contributing positively, while refractivity of group present at 2 position of aryl group present on 2 position of cyclopentenone ring contributes negatively to the biological activity.

-log IC₅₀ = 0.409 (±0.130) Total Hydrophobicity – 0.233 (±0.060) Refractivity +

0.949

n =18, r =0.859 F-test = 21.051, r² adj. = 0.702, S= 0.129,

n = Number of compounds

Model - Q

This model considers three variables namely total Hydrophobicity refractivity at Site 1 (Para position of aryl group present at 2 position of cyclopentenone ring) and at Site 2 (sulphonyl methyl group). The total Hydrophobicity and Refractivity at site 2 contribute positively and refractivity at site 1 contributes negatively to the biological activity.

-log IC₅₀ = 0.431 (±0.118) Total Hydrophobicity – 0.299 (±0.064) Refractivity Site 1

+ 0.178 (±0.068) Refractivity Site 2 + 0.970

n = 21, r =0.875 F-test = 18.492, r² adj. = 0.724, S= 0.321,

From comparative studies of both models it can be concluded that model Q is more reliable for following reasons.

Ø It considers all 21 compounds of training set.

Ø The predictivity of this model was tested by predicting activities of test set compounds and correlating it with experimental activities. The correlation was 0.808.

Ø The match of this model is ³0.64 which implies that superimposition of biophoric site of all compounds is 64%. The following diagram shows various primary biophoric sites and secondary sites of the compounds in model Q.

ACKNOWLEDGEMENT

Authors are thankful to CDRI, Lucknow for providing facilities for this work and valuable guidance.

Table I: Structure and Biological Activity of 2,3 Diaryl Cyclopentenones

R = Substituents on aryl ring, IC₅₀ = Inhibitory concentration for 50% activity,

* Compounds reported in Original Article⁹

Table II: The Descriptors for QSAR Studies.

Table III: Internal Test Set Compounds

Table IV: 3-D Quantitative Models.

Table V: Comparison of Activities of Test Set Compounds in Selected Models

Table VI: Experimental, Predicted and Calculated Biological Activities of Compounds from Model Q and R

Fig 1: Experimental Vs Predicted Activity of Model Q

Fig 2: Experimental Vs Calculated Activity of Model Q

Fig 3: Experimental Vs Predicted Activity of Model R

Fig 4: Experimental Vs Calculated Activity of Model R

{mospagebreak title=References}

REFRENCES

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{mospagebreak title=About Authors}

Prof. Kane R.N.*, Mr. Bumrela S.B. and Dr. Sawant S. D.

*Author for correspondence

Prof. Kane R. N. , completed M. Pharm in Medicinal & Pharmaceutical Chemistry from Dept of Pharmacy, S.G.S.I.T.S. Indore, Rajiv Gandhi Technological University, Bhopal. Dissertation topic “3-D QSAR Analysis of 2,3 diaryl cyclopentenones as selective Cyclooxygenase 2 inhibitor”.11 years experience as lecturer and 3 years experience as Principal. Presently working as Principal at Sinhgad Institute of Pharmaceutical Sciences, Lonavala.

Various papers are presented in Indian Pharmaceutical Congress (IPC) and International Convention of Association of Pharmaceutical Teachers of India (APTI). Life Member of APTI. Area of interest: Novel Drug Delivery System.

Corresponding address:

Kane R.N.

Sinhgad Technical Education Society’s Sinhgad Institute of Pharmaceutical
Sciences, Off Mumbai-Pune Expressway, Kusgaon (Bk), Lonavala, Pin: 410401, Phone:
02114 280076

Mr. Bumrela S. B, completed M. Pharm in Biopharmaceutics from
Govt. College of Pharmacy, Karad in 2001. Presently working as Lecturer
at Sinhgad Institute of Pharmaceutical Sciences, Lonavala. He presented various
papers in Indian Pharmaceutical Congress (IPC) and International Convention
of Association of Pharmaceutical Teachers of India (APTI). He is life Member
of APTI. His areas of interest include Novel Drug Delivery System and Clinical
Pharmacology.

Dr. Sawant S. D, Principal of STES Sinhgad Institute of Pharmaceutical sciences, Phd in Pharmaceutical Sciences, twelve years of academic experince,worked as Manager in Sanjivani Research centre.He is member of several national & international Pharmaceuutical Associations.