NEW PHENOTHIAZINE DERIVATIVE DESIGNED ACCORDING TO LIPINSKI’S RULE OF FIVE AND ITS VARIANTS
Bint-e-Haider, Muhammad Qaiser, Hafsa Faizi
Faculty of Pharmacy, University of Sargodha, Sargodha 40100 Pakistan
Keywords: Drug designing, Therapeutic derivative, Phenothiazine
Abstract

Some of the new 10H phenothiazine derivatives had been synthesized for their anti psychotic activity as dopamine antagonists. They had been synthesized with the help of software Marvin sketch. 10 parameters were analyzed for each of them which could make them drug like molecule. All parameters were found to be within range. Newly designed structures justify all the aspects of anti psychotic activity by satisfying Lipinski’s Rule. Three carbon distance from two amine atoms keeps the polar surface area within range (>10). Log P value and conformational energy of these derivatives shows that they are structurally constrained molecules. They have also satisfied the stereo chemistry and hence safer derivatives. The limit for total numbers of atoms and H-bond donor and Acceptor are also seem to be fulfilled. So these derivatives have maximum chances that they could be drug like molecules which may have valuable anti psychotic activity. They could be investigated further for clinical use in conditions like schizophrenia, mania and other psychotic disorders.

Article Information

Identifiers and Pagination:
Year:2013
Volume:5
First Page:34
Last Page:40
Publisher Id:JAppPharm (2013 ). 5. 34-40
Article History:
Received:February 17, 2013
Accepted:March 25, 2013
Collection year:2013
First Published:April 1, 2013

INTRODUCTION:

Phenothiazine is a group of anti psychotic drugs. Synthesis of phenothiazine was started in 1883. In early era phenothiazine dyes were discovered like in 1877. These dyes were used to dye cellulose and fibers. But this drug is of pharmacological importance because its activities as therapeutic agent came to be known when phenothiazines were synthesized in 1950s, a 10-substituted drug. Phenothiazine has anti septic, anti helminthes, and insecticidal effect. Most prominent use of this drug is as tranquilizer because it has defused anti psychotic effects.  [1] Also reports to have anti cancer and antiviral effects [2]

                                                  

Chemically phenothiazine can interact with many physiological processes in body and for treatment of number of medical conditions. Its chemical structure gives an important base for developing new drug like molecules. New 10 H phenothiazines were synthesized previously with different biological activities due to heterocyclic structure. [2] Phenothiazines structurally consist of two benzene rings connected in tri cyclic system with the help of nitrogen and sulphur. [2] Phenothiazine also acts against many bacteria like Mycobacterium tuberculosis [3]. Many derivatives of phenothiazine inhibits the cleavage activity noncompetitively of MALT-1 (mucosa associated lymphoid tissues) hence showing anti cancer activity [4]. Phenothiazine as amino alkyl molecules has anti histaminic action by antagonizing H1 receptor. [5]. This drug has affinity for dopaminergic D1 and D2 receptor acting as anti psychotic drugs. [6]

Phenothiazine is structurally stable crystalline solid having melting point 185.1°C. It is a semi solid having activation energy 1.6 e.V. It is 10-(2-pyridyl)-5H-pyrido [3,2-b][1,4]benzothiazine. Its molecular configuration depicts that it has sp-3 hybridization and arrangement is planar or tetragonal.[1] Structures of phenothiazines can be analyzed by NMR, mass spectroscopy[7] and partitioning through HPLC [1]

 

METHODOLOGY

The methodology used in this study was software named as MarvinSketch 5.12.1, build date 19th March, 2013.  Internal build ID 5.12.1_b94. Its maximum memory is 247.5M. It runs on JAVA (oracle corporation java 1.7.0_09). This software was used during study and different aspects were analyzed. The software has greatly helped in drug designing process due to its accuracy in structure naming and placing of functional groups was done very effectively. The IUPAC naming system of this software prevents wrong structure forming i.e if any moiety is placed wrongly then the naming system clearly indicates that the structure is not desired one. Placing of desired bond on desired place is so simple that there is no chance of error.

The major important aspect of this software is that the designer can easily study the properties of drug and structures like polarity, log P, No. of atoms, Stereo chemistry, Tautomerism, Refractivity, partitioning, NMR, Geometry etc. We had studied these properties according to Lipinski’s Rule. This software has structure checker system that can identify the errors and recommend for change.

 

RESULTS AND DISCUSSION

The final results obtained from Marvin Sketch are being examined and found appropriate for further pharmaco-therapeutical evaluation. The new derivatives qualify all the parameters of Llipinski’s rule of five and its variants.

.                  

                        

PROPERTIES OF DRUG LIKE MOLECULE ACCORDING TO LIPINSKI RULE AND ITS VARIANTS

No

Molecular Mass

No.

of atom

Log P

Polar surface area

Conformat-ional

Energy

Kcal/mol

  H-bond

 acceptor

   Isotope         formula

H

bond Donor

Stereo

Chemistry

Refractivity

Kjoule

1

363.3

40

4.7

 6.48

 67.7-74.8

     2

C17H19Br2S

0

Isomer=1

      96.5

2

393.4

49

4.7

 9.72

 86.0-96.5

     3

C20H22F3S

0

Isomer=1

       105.7

3

332.8

43

4.8

 6.48

 73.7-81.0

     2

C18H21ClNS

0

Isomer=1

       98.5

4

349.2

37

4.0

 6.48

 62.5-66.5

     2

C16H17N2S

0

Isomer=1

       91.59

5

298.4

43

3.9

 6.48

 67.3-75.5

     2

C18H22N2S

1

Isomer=2

       101.07

6

338.5

50

4.7

 6.48

 74.9-82.9

     2

C21H26N2S

1

Isomer=1

        105.5

7

312.4

46

4.2

 6.48

 71.7-81.0

     2

C19H24N2S

1

Isomer=1

        98.1

8

310.4

44

4.3

 6.48

 73.5-85.3

     2

C19H22N2S

0

Isomer=1

        96.4

9

335.4

45

3.9

 9.72

 90.3-95.4

     3

C20H21N3S

0

Isomer=1

       103.7

 

We tried to design new phenothiazines derivatives which have potential to become drug like molecule and ultimately clinically useful drug. For each of the newly designed drug the 10 parameters which are necessary for an organic molecule to become drug like molecule were studied. All newly designed phenothiazine was found to have the properties which could make them clinically useful drug. The parameter tested was basically the Lipinski’s rule and its variants by using the software like Marvin Sketch. These compounds are drug like molecules which could become clinically useful anti psychotic drug.

Jack [6] reported Phenothiazine carry lipophilic specificity. In structure 3-C molecules from one nitrogen to second nitrogen is very important for psychotic treatment as its binding with dopamine receptor becomes easy and antagonizes them [6]. Two amine (N) present in structure have their importance in receptor affinity. [6] The basic structure of phenothiazine necessary for anti psychotic activity keeping in view SAR of drug was maintained during the study. In literature only basic structure was explained for dopamine antagonizing activity but here new moieties were actually applied and their properties were studied.

Sinha et al., [2] reported about antiviral, anti cancer and other biological activities of phenothiazine derivatives, according to her small change in moieties may cause greater change in pharmacological and therapeutic performance. Her worked was focused mainly on antimicrobial, anti inflammatory, antiviral and anti histaminic activity of phenothiazine, but no discussion on anti psychotic activity of this drug. Keeping in view this study the therapeutic work of phenothiazines derivatives were screened by making small manipulations to main structure and main focus was their antipsychotic activity.

Upendra et al., [7] reported the analgesic activity of new derivatives of phenothiazine by adding azetidinyl thiazolyl and azetidinyl oxazolyl moieties on phenothiazine nucleus thus proving that substitution on phenothiazine aggravates its therapeutic properties. However this was a complex study and synthesis was difficult because anti inflammatory and ulcerogenic activity was also studied. Focusing on this literature new drug like molecules designed with therapeutic effect as anti psychotic but simple and basic study was carried out by adding basic functional groups on nucleus.

 

CONCLUSION:

Newly designed structures justify all the aspects of anti psychotic activity by satisfying Lipinski’s Rule. Three carbon distance from two amine atoms keeps the polar surface area within range (>10). Log P value and conformational energy of these derivatives shows that they are structurally constrained molecules. They have also satisfied the stereo chemistry and hence safer derivatives. The limit for total numbers of atoms and H-bond donor and Acceptor are also seem to be fulfilled. So these derivatives have maximum chances that they could be drug like molecules which may have valuable anti psychotic activity. They could be investigated further for schizophrenia, mania and psychotic disorders in clinical practice.

 

FURTHER STUDY

In the next research work we will try to study them on animal models for anti psychotic activity.

 

RECOMMENDATION  

1.      These drugs like molecules may be synthesized and formulated appropriately.

2.      Their pharmacological and toxicological activities could be performed on animal models before clinical trials.

 

ACKNOWLEDGEMENT

Dr.Taha Nazir B.Pharm., M.Phil., Ph.D., Scientific Executive, ICDTD Inc., SK Canada.

 

REFERENCES:

1.      Ulrich.H, Houben weyl, “6-Ring structure with two different heteroatoms”volume E9, P.No 510-553

2.      Sinha shweta, Pandeya S.N, Verma Anupam, Yadav Deepeka (2011), “Synthesis And Biological Activities of Phenothiazine Derivatives”, International Journal of Research in Ayurveda And Pharmacy ISSN 2229-3566, 2(4) 1130-1137,

3.      Ashley J. Warman 1, Teresa S. Rito 1, Nicholas E. Fisher1, Darren M.Moss1, Neil G.Berry2, Paul M. O’Neill2, Stephen A. Ward1, and Giancarlo A.Biaginil, (2012) “Anti Tubular Pharmacodynamics of Phenothiazine”,Oxford Journal,Medicine,Journal of Antimicrobial Chemotherapy, Advance Access 10.1093/jac/dks483

4.      Daniel Nagel, Stefani Spranger, Michelle Vincendeau. Michael Grau, Silke Raffegerst, Bernhard Kloo, Daniela Hlahla, Martin Neuenschwander, Jens Petervon Kries, Kamyar Handian, Bernd Dorken, Peter Lenz, Georg Lenz, Dolores J. Schendel, Daniel Krappmann, (2012), “Pharmacologic Inhibition of MALT1 Protease by Phenothiazines as a Therapeutic Approach for the Treatment of Aggressive ABC-DLBCL” Cancer Cell, Volume 22, Issue 6.

5.      Jack De Ruitter (2001), “Histamine H1-receptor antagonists: antihistaminic agents”, Principles of Drug Action 2, Fall 2001.

6.      Jack De Ruitter (2001), “Dopamine Antagonists: Phenothiazine/Thioxanthene SAR”, Principles of Drug Action 2, Fall 2001.

Upendra Kumar Kushwaha*, Yashovardhan*, Sudhir Kumar Bhati** and Ashok Kumar**. (Jul-Sept 2010), “Synthesis Of New 10-Substituted Phenothiazines as Anti-inflammatory and Analgesic agents.” International Journal of Pharma and Bio Sciences, ISSN 0975-6299, Vol.1/Issue-3/Jul-Sep.2010.


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Editor in Chief
Prof. Dr. Cornelia M. Keck (Philipps-Universität Marburg)
Marburg, Germany

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Welcome to the research group of Prof. Dr. Cornelia M. Keck in Marburg. Cornelia M. Keck is a pharmacist and obtained her PhD in 2006 from the Freie Universität (FU) in Berlin. In 2009 she was appointed as Adjunct Professor for Pharmaceutical and Nutritional Nanotechnology at the University Putra Malaysia (UPM) and in 2011 she obtained her Venia legendi (Habilitation) at the Freie Universität Berlin and was appointed as a Professor for Pharmacology and Pharmaceutics at the University of Applied Sciences Kaiserslautern. Since 2016 she is Professor of Pharmaceutics and Biopharmaceutics at the Philipps-Universität Marburg. Her field of research is the development and characterization of innovative nanocarriers for improved delivery of poorly soluble actives for healthcare and cosmetics. Prof. Keck is executive board member of the German Association of Nanotechnology (Deutscher Verband Nanotechnologie), Vize-chairman of the unit „Dermocosmetics“ at the German Society of Dermopharmacy, active member in many pharmaceutical societies and member of the BfR Committee for Cosmetics at the Federal Institute for Risk Assessment (BfR).

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Abbreviation: J App Pharm
doi: http://dx.doi.org/10.21065/19204159
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