Synthesis of API’s and API’s based Derivative

implication of APIs and APIs ground Derivative human activity of Proposed ProjectEfficient synthesis of APIs and APIs based Derivative for their Structure Activity Relationship and Pharmacokinetics ProfileProject DetailsProject thicksetThis project concern with the establishment of organic synthesis facilities in Department of Chemistry, UNIVERSITY OF KARACHI. The established facilities result 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 go out focus on the establishment of synthetic organic laboratory, the synthesis of the two APIs (Secnidazole Atenolol). We atomic number 18 requiring the chase basic facilities which we want to establish by this research project.Facilities infallible forOrganic SynthesisFuming HOODs for save, non-hazardous and smooth working at the moment.Inert atmosphere working contains since umpteen organic reactions requires inert condition.Safety equipments i.e. firefighting equipments, washing shower in case of chemic accident and first aid facilities.(UPS) as regular index break pot results in the unsuccessful reactions and causing faults in the electronic instruments.UV lamp as processing of many reaction monitor under UV light.lap evaporatorPartial availability of glass wares.MAS-II Microwave workstation for repaid synthesis of genus Apis.Proposed Goals / ObjectivesHypothesis / Basis of researchThe purpose of this project is to setup a laboratory which can foundation (Organic Synthesis) and synthesize (Organic Synthesis) the APIs for the local Pharmaceutical industry along with the establishment of the required facilities.The fol upseting APIs will be synthesized.atenololEfficient Synthesis of Atenolol.Synthesis of Atenolol based derivatives for Structure-Activity Relationship Studies (severe acute respiratory syndrome) and their pharmacokinetics profileSECNIDAZOLEEfficient Synthesis of SecnidazoleSynthesis of Secnidazole based derivatives for St ructure-Activity Relationship Studies (SARS) and their pharmacokinetics profileGoals / ObjectivesBoost up economy of Pakistan semisynthetic solution for local industry.Provide sufficient amount of these drugs to common people.INTRODUCTIONAPI 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 prospect 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 to a greater extent efficacious synthesis of complex molecules. In th is project we rich person design the synthesis of the following APIsATENOLOLEfficient Synthesis of Atenolol.Synthesis of Atenolol based derivatives for Structure-Activity Relationship Studies (SARS) and their pharmacokinetics profileSECNIDAZOLEEfficient Synthesis of SecnidazoleSynthesis of Secnidazole based derivatives for Structure-Activity Relationship Studies (SARS) and their pharmacokinetics profile4a) background of the Research Problems to be addressedSecnidazole (Part A)Efficient Synthesis of SecnidazoleSecnidazole 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 diaphragmontitis. . All nitroimidazoles are synthetic drugs such as metron idazole. 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 StructureIUPAC Name1-(2-methyl-5-nitro-1H-imidazol-1-yl) propan-2-olFigure 2 Proposed Two-Step Synthesis street for SecnidazoleAfter 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 profilePharmacological 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 57% 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. Thats why in this project our site is to synthesize the prodrug for its break dance mode of action and their structure activity relationship and their pharmacokinetics profile.ATENOLOL (Part B)Efficient Synthesis of AtenololAtenolol (ATN) belongs to the class of drug called beta-blockers. Beta-blockers (beta adrenoreceptor antagonists) are basically belligerent inhibitor thats 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 hearts 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 Name2-4-2-hydroxy-3-(propan-2-ylamino) propoxy phenyl acetamideFigure 2 Proposed Two-Step Synthesis route for AtenololThe 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) c onfirmationSynthesis of Atenolol based derivatives for Structure-Activity Relationship Studies (SARS) and their pharmacokinetics profileOn the basis of the importance of prodrug (mention above part) our aim is to synthesize the prodrug for its advance mode of action and their structure activity relationship and their pharmacokinetics profile.4B.RESEARCH PLAN/ METHODOLOGY SCHEDULE/PHASINGEstablishment of Organic Synthesis Facilities In the scratch line 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 stripped 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 profileSynthesis of ATENOLOL In the perio d of 7th to 9th month of the project efficient synthesis of atenolol will be doneSynthesis 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 profileSummarize results and expand to late 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 set about during this project.4c) ReferencesSecnidazole (Part A)Larina, Lyudmila, and Valentin Lopyrev.Nitroazoles synthesis, structure and applications. New York Springer, 2009.Crozet, Maxime D., Cline Botta, Monique Gasquet, Christophe Curti, Vincent Rmusat, Sbastien Hutter, Olivier Chapelle, Nadine Azas, Michel De Mo, and Patrice Vanelle. Lowering of 5-nitroimidazoles mutagenicity towards optimal antiparasitic pharmacophore.European journal of medicinal chemistry44, no. 2 (2009) 653-659Wang, She-Feng, Yong Yin, Fan g Qiao, Xun Wu, Shao Sha, Li Zhang, and Hai-Liang Zhu. Synthesis, molecular(a) 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 coordination compound hydrogels.Carbohydrate polymers106 (2014) 109-120.Elias, P. curefor learny.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.Chemica l 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) 3855-3862IMPACT OF PROPOSED RESEARCHThe 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 PeriodDESCRIPTIONPER YEARAmount (in million Rs)A. Salaries and HonorariumPI One Month/Year of Basic Pay 1040000.104 (208000) assimilator Ships 20,000.00 per month (two)4800000.48 (480000)Secretariat StaffPart-time Lab Attendant 1500 PM180000.018(18000)Subtotal (A)6020000.602(602000)B. Permanent EquipmentGeneral purpose fume hood Pkr 150,000/= (two)3000000.600(600000)The rotary evaporator r 3 focuses and accessories Pkr 150000015000001.500(1500000)Jacketed reaction apparatus Pkr 169650/= (one)1696500.1695(169650)Glassware, hotplates, stirrer, etc.2500000.250(250000)Laptop (dell core 2i)500000.050(50000)General lab update i.e. Ups and power supply solutions2500000.250(250000)Mas II microwave synthesis system $8000/= (one)8000000.800(800000)Subtotal (B)33196503.319650 (3319650)C. replaceable SuppliesChemicals and solvents3000000.300(300000)General lab expendituresmyriad00.100(100000)Spectroscopy techniques2500000.250(250000)Subtotal (C)6500000.65(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)500000.050(50000)Stationary/Contingency (10,000/- per year)100000.010(10000)Participation in local conferences, workshops and winter summer schools by PI and students100000.010(10000)Audit Fee (Max. Rs 10,000)100000.010(10000)Accountant Fee (Max. Rs. 10,000)100000.010(10000)Subtotal (D)900000.090(90000) gilded Total(A + B + C + D)46616504.661650(4661650)JUSTIFICATIONSalaries AllowancesTwo 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 make to sort part time jobs to meet their day to day expensePart-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 justify to compensate their work with an honorarium.Permanent EquipmentThe Rotary Evaporator and accessories (one) Many organic reactions ar e in liquid pattern and require much more time to evaporate on room temperature thats 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 hoodsJacketed 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 apparatusGlassware, Hotplates, Stirrer, refwork etc These are the basics requirement for organic synthesis as well as we have shortage of these basics necessitate thats why we need theseGeneral 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 suppliesChemicals and solvents These play k ey role in all reaction either organic or inorganic and no one can performed reaction without this so these funding are fully justifiedGeneral Lab Expenditures these are the basic need for researcher to meet day to day expensesParticipation 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