Title of Proposed Project:
Efficient synthesis of API’s and API’s based Derivative for their Structure Activity Relationship and Pharmacokinetics Profile
Project Details

Project Summary

This project concern with the establishment of organic synthesis facilities in Department of Chemistry, UNIVERSITY OF KARACHI. The established facilities will be used for the training of BS/M.Sc./MS/M.Phil. And Ph.D. scholars in the field of Organic Synthesis. In this project we will focus on the establishment of synthetic organic laboratory, the synthesis of the two API’s (Secnidazole & Atenolol). We are requiring the following basic facilities which we want to establish by this research project.
Facilities required for:
Organic Synthesis

Fuming HOODs for save, non-hazardous and smooth working at the moment.
Inert atmosphere working conditions since many organic reactions requires inert condition.
Safety equipment’s i.e. firefighting equipment’s, washing shower in case of chemical accident and first aid facilities.
(UPS) as regular power breakdown results in the unsuccessful reactions and causing faults in the electronic instruments.
UV lamp as processing of many reaction monitor under UV light.
Rotary evaporator
Partial availability of glass wares.
MAS-II Microwave workstation for repaid synthesis of APIs.

Proposed Goals / Objectives

Hypothesis / Basis of research

The purpose of this project is to setup a laboratory which can design (Organic Synthesis) and synthesize (Organic Synthesis) the APIs for the local Pharmaceutical industry along with the establishment of the required facilities.
The following APIs will be synthesized.

ATENOLOL

Efficient Synthesis of Atenolol.
Synthesis of Atenolol based derivatives for Structure-Activity Relationship Studies (SARS) and their pharmacokinetics profile

SECNIDAZOLE

Efficient Synthesis of Secnidazole
Synthesis of Secnidazole based derivatives for Structure-Activity Relationship Studies (SARS) and their pharmacokinetics profile

Goals / Objectives

Boost up economy of Pakistan
Synthetic solution for local industry.
Provide sufficient amount of these drugs to common people.

INTRODUCTION

API stands for active pharmaceutical ingredients and its covers a lot of pharmaceutically active compounds which has great importance in industry as well as to common people as the insufficiency of these drugs causes hundreds of death. Due to the importance of API we decided to work with the synthesis of API as it will create the impact of API research on national level. The synthesis of API could decrease the import bill of such active ingredient in Pakistan and also opens the opportunity of job. This project could provide a platform to save the foreign currency reserves and supply sufficient amount of drugs to common people at low cost.
Ours Efforts will be enabling to purpose the more efficient synthesis of complex molecules. In this project we have design the synthesis of the following APIs

ATENOLOL

Efficient Synthesis of Atenolol.
Synthesis of Atenolol based derivatives for Structure-Activity Relationship Studies (SARS) and their pharmacokinetics profile

SECNIDAZOLE

Efficient Synthesis of Secnidazole
Synthesis of Secnidazole based derivatives for Structure-Activity Relationship Studies (SARS) and their pharmacokinetics profile

4a) Background of the Research Problems to be addressed
Secnidazole (Part: A)

Efficient Synthesis of Secnidazole

Secnidazole is a molecule which belongs to the class of 5-nitroimidazole and it is considerably more effective than other imidazole drugs. It is the important API required for the local industry. However it has been used for the treatment of amoebiasis, giardiasis, urogenital trichomoniasis and nonspecific bacterial vaginosis and also a gel formulation of secnidazole was developed for the treatment of periodontitis. . All nitroimidazoles are synthetic drugs such as metronidazole. Tinidazole, dimetridazole, secnidazole and ornidazole. Among all these we selected secnidazole because of its High efficacy. Secinidazole is the mainly use for antiprotozoal activity and its single dose possess three days anti protozoal activity.

Figure 1: Chemical Structure
IUPAC Name:1-(2-methyl-5-nitro-1H-imidazol-1-yl) propan-2-ol
Figure 2: Proposed Two-Step Synthesis route for Secnidazole
After observing the reaction condition and UV-Vis absorption, FTIR, ESI-MS and NMR results. The purposed scheme will be optimized.

Synthesis of Secnidazole based derivatives for Structure-Activity Relationship Studies (SARS) and their pharmacokinetics profile

Pharmacological and pharmacokinetic properties of existing drugs can be enhanced by chemical modifications. A prodrug (drug transporter) formation is a great approach to improve and modify the physio chemical properties of the drug, boost up its concentration at the site of action, extend its period of action and decrease its toxicity. Regarding 5–7% of drugs approved worldwide are categorized as prodrug. Prodrugs are the reversible, inactive or less active derivatives of a drug. Prodrugs are hydrolyzed either by enzymatically or non-enzymatically to discharge parent drug while the co-drugs (mutual prodrug) are the special type of prodrug in which two or more pharmacologically active pro moieties exist via chemical bond to release two or more parent drugs upon the cleavage of bond by enzymatically or chemically. The variety of chemical linkages used in the formation of Prodrugs. Although the ester formation is common followed by imides, amide and carbamate derivative. That’s why in this project our aim is to synthesize the prodrug for its better mode of action and their structure activity relationship and their pharmacokinetics profile.
ATENOLOL (Part: B)

Efficient Synthesis of Atenolol

Atenolol (ATN) belongs to the class of drug called beta-blockers. Beta-blockers (beta adrenoreceptor antagonists) are basically competitive inhibitor that’s inhibits the action of stimulating hormones on beta adrenergic receptors in the nervous system. Atenolol works by competing for receptors sites on cardiac muscle. This slow down the strength of heart‘s contractions and reduce its oxygen requirements and the volume of blood it has to pump. Atenolol is one of the extensive used active pharmaceutical ingredients (API) for the treatment of Hypertension, myocardial infarction (Heart attack), Arrhythmias (rhythms disorder), Angina (chest pain) and disorder arising from decreased circulation of blood.

Figure 1: Chemical Structure
IUPAC Name:2-[4-[2-hydroxy-3-(propan-2-ylamino) propoxy] phenyl] acetamide
Figure 2: Proposed Two-Step Synthesis route for Atenolol
The stereochemistry is important for any molecules. In atenolol (S) – isomer is important for its activity the opposite (R) – enantiomer may be responsible for the side effects. There have been considerable efforts done in the preparation of enantiomerically pure(S) confirmation

Synthesis of Atenolol based derivatives for Structure-Activity Relationship Studies (SARS) and their pharmacokinetics profile

On the basis of the importance of prodrug (mention above part) our aim is to synthesize the prodrug for its better mode of action and their structure activity relationship and their pharmacokinetics profile.
4B.RESEARCH PLAN/ METHODOLOGY: SCHEDULE/PHASING

Establishment of Organic Synthesis Facilities: In the starting 1st months of this project all the basic and reaction requirement apparatus and glassware will be installing.

Efficient Synthesis of SECNIDAZOLE: After initialization, the starting 3 months will be utilized on the proposed and modified efficient synthesis of Secnidazole to get the maximum yield of required API at minimum cost.

Synthesis of SECNIDAZOLE based derivatives for SARS: In the 5th and 6th month modification on the molecule of Secnidazole will be applied and study their pharmacokinetics profile

Synthesis of ATENOLOL: In the period of 7th to 9th month of the project efficient synthesis of atenolol will be done

Synthesis of ATENOLOL based derivatives for SARS: In the period of 10th to 11th month of the project timeline, derivatization of atenolol will be carried out and studied their pharmacokinetics profile

Summarize results and expand to new project: At the end month of this project timeline a final project report will be submitted along with findings. Also discuss the achievements and problems faced during this project.

4c) References
Secnidazole (Part: A)

Larina, Lyudmila, and Valentin Lopyrev.Nitroazoles: synthesis, structure and applications. New York: Springer, 2009.

Crozet, Maxime D., Céline Botta, Monique Gasquet, Christophe Curti, Vincent Rémusat, Sébastien Hutter, Olivier Chapelle, Nadine Azas, Michel De Méo, and Patrice Vanelle. “Lowering of 5-nitroimidazole’s mutagenicity: towards optimal antiparasitic pharmacophore.”European journal of medicinal chemistry44, no. 2 (2009): 653-659

Wang, She-Feng, Yong Yin, Fang Qiao, Xun Wu, Shao Sha, Li Zhang, and Hai-Liang Zhu. “Synthesis, molecular docking and biological evaluation of metronidazole derivatives containing piperazine skeleton as potential antibacterial agents.”Bioorganic & medicinal chemistry22, no. 8 (2014): 2409-2415.

Samanta, Himadri Sekhar, and Samit Kumar Ray. “Controlled release of tinidazole and theophylline from chitosan based composite hydrogels.”Carbohydrate polymers106 (2014): 109-120.

Elias, P. cureforneedy.com 2009, 1-11.

Shahid, Hafiz Abdullah, Ejaz Hussain, Sajid Jahangir, and Sammer Yousuf. “1-(2-Methyl-5-nitro-1H-imidazol-1-yl) propan-2-yl acetate.”Acta Crystallographica Section E: Structure Reports Online70, no. 3 (2014): o294-o294.

Atenolol (Part: B)

Chaudhari, Vilas, Syed Hussain, and Milind Ubale. “International Journal of Chemical Studies.”

Kitaori, Kazuhiro, Yoshikazu TAKEHIRA, Yoshiro FURUKAWA, Hiroshi YOSHIMOTO, and Junzo OTERA. “A practical synthesis of optically active atenolol from chiral epichlorohydrin.”Chemical and pharmaceutical bulletin45, no. 2 (1997): 412-414.

Darnle, Subhash V., Prashant N. Patil, and Manikrao M. Salunkhe. “Chemoenzymatic synthesis of (R)-and (S)-atenolol and propranolol employing lipase catalyzed enantioselective esterification and hydrolysis.”Synthetic communications29, no. 22 (1999): 3855-3862

IMPACT OF PROPOSED RESEARCH

The impact of this project will boost up the economy of Pakistan and will decrease the import bill of Pakistan and also increases the exportation. The project also aims to train the man power and create the skillful hand that can provide the better solution to our local industry. This project also creates the networking between the local industry and researcher. This project also contributes in the providing of the medicine to common people at minimum cost.

Estimated Budget For The Proposed Research Period:

DESCRIPTION

PER YEAR

Amount (in million Rs)

A. Salaries and Honorarium

PI: One Month/Year of Basic Pay @

104000

0.104 (208000)

Student Ships @ 20,000.00 per month (two)

480000

0.48 (480000)

Secretariat Staff

Part-time Lab Attendant @ 1500 PM

18000

0.018
(18000)

Subtotal: (A)

602000

0.602
(602000)

B. Permanent Equipment

General purpose fume hood @ Pkr 150,000/= (two)

300000

0.600
(600000)

The rotary evaporator ® r 3 focuses and accessories @ Pkr 1500000

1500000

1.500
(1500000)

Jacketed reaction apparatus @ Pkr 169650/= (one)

169650

0.1695
(169650)

Glassware, hotplates, stirrer, etc.

250000

0.250
(250000)

Laptop (dell core 2i)

50000
 

0.050
(50000)

General lab update i.e. Ups and power supply solutions

250000
 

0.250
(250000)

Mas II: microwave synthesis system @ $8000/= (one)

800000

0.800
(800000)

Subtotal: (B)

3319650

3.319650 (3319650)

C. Expendable Supplies

Chemicals and solvents
 

300000

0.300
(300000)

General lab expenditures
 

100000

0.100
(100000)

Spectroscopy techniques

250000

0.250
(250000)

Subtotal: (C)
 

650000

0.65
(650000)

D. Others (Literature, documentation, information, online literature search, contingencies, postage, Local Travel Miscellaneous etc).

Journal Publication Fee / Online Material (up to Rs.50,000)

50000

0.050
(50000)

Stationary/Contingency (10,000/- per year)

10000

0.010
(10000)

Participation in local conferences, workshops and winter summer schools by PI and students

10000

0.010
(10000)

Audit Fee (Max. Rs 10,000)

10000
 

0.010
(10000)

Accountant Fee (Max. Rs. 10,000)

10000

0.010
(10000)

Subtotal: (D)
 

90000

0.090
(90000)

Grand Total
(A + B + C + D):

4661650

4.661650
(4661650)

JUSTIFICATION

Salaries & Allowances

Two Studentships @ 20,000.00 per month (PM): It is very necessary that at least two full time studentships available to students so that students can perform their work with piece of mind so that they have no need to sort part time jobs to meet their day to day expense
Part-time Lab Attendant @ 1500 PM: During period of project operations different kind of tasks are assigned to Lab Attendant in addition to their normal job responsibilities. Therefore it is justified to compensate their work with an honorarium.

Permanent Equipment:

The Rotary Evaporator and accessories (one): Many organic reactions are in liquid phase and require much more time to evaporate on room temperature that’s why to save time and fast reaction process need rotary evaporator.
General Purpose Fume Hood: As many organic reaction, chemicals and solvents are hazardous to human health. For safety and precautionary step need two fuming hoods
Jacketed Reaction Apparatus: It is the temperature control apparatus. As many reaction are temperature dependent and monitor through varying temperature. to make reaction efficient we need jacketed reaction apparatus
Glassware, Hotplates, Stirrer, refwork etc: These are the basics requirement for organic synthesis as well as we have shortage of these basics needs that’s why we need these
General lab updates i.e. UPS and Power Supply solutions: Regular breakdown of power supply has resulted in the failure of organic reactions as well as damage of electronic appliances. Therefore a need to establish backup of power supply.

Expendable supplies

Chemicals and solvents: These play key role in all reaction either organic or inorganic and no one can performed reaction without this so these funding are fully justified
General Lab Expenditures: these are the basic need for researcher to meet day to day expenses

Participation in local conferences, workshops and winter/summer schools by PI and students: These funding are required to communicate our work on national and international level. Also learn gain information from their experience