Pharm-714 Medicinal Chemistry Lecture Notes PDF

PHARM-714 MEDICINAL CHEMISTRY LECTURES PREPARED BY DR. TANIA MIRZA Chairperson & Associate Professor Department of Pharmaceutical Chemistry  LESSON 1 ANTITUBERCULAR AGENTS  CONTENTS  TUBERCULOSIS  TYPES OF TUBERCULOSIS  ANTITUBERCULAR DRUGS  AVAILABL...

PHARM-714 MEDICINAL CHEMISTRY LECTURES PREPARED BY DR. TANIA MIRZA Chairperson & Associate Professor Department of Pharmaceutical Chemistry  LESSON 1 ANTITUBERCULAR AGENTS  CONTENTS  TUBERCULOSIS  TYPES OF TUBERCULOSIS  ANTITUBERCULAR DRUGS  AVAILABLE BRANDS  REFRENCES TUBERCULOSIS (TB)  DEFINITION: An infectious bacterial disease characterized by the growth of nodules (tubercles) in the tissues, especially the lungs.  ETIOLOGY: TB is caused by Mycobacterium species mainly by Mycobacterium tuberculi, other strains which causes TB are M.avium, M.bovis, M.hominis, etc.  TRANSMISSION: It is spread through the air from one person to another via – Inhalation – Ingestion – Inoculation – Trans placental routes TB……..  M. tuberculosis has an unusual, waxy coating on its cell surface primarily due to the presence of mycolic acid. This coating makes the cells impervious to Gram staining, and as a result, M. tuberculosis can appear either Gram-negative or Gram-positive.  The concentrations of oxygenases greater in alveoli of lungs. Hence Mycobacterium species majorly reside in alveoli of lungs, and as it is strict aerobe strictly thrives best in tissues with high Oxygen tension such as in the apex of the lung.  Types of tuberculosis: 1. Pulmonary TB 2. Genitourinary TB 3. Tuberculous meningitis 4. Miliary TB  ANTITUBERCULAR DRUGS Hypothetical M.O.A. of ATB Agents ANTITB DRUGS…………… 1. ISONICOTINIC ACID HYDRAZIDE (INH)  Isoniazid, also known as phthiazide or hydrazid, belongs to the class of organic compounds known as pyridine carboxylic acids and derivatives.  Pyridine carboxylic acids (isonicotinic acid) and derivatives are compounds containing a pyridine ring bearing a carboxylic acid group or a derivative thereof.  INH is a prodrug i.e., activated on the surface of M. tuberculosis by katG enzyme to isonicotinic acid.  Isonicotinic acid inhibits cell wall mycolic acid. ANTITB DRUGS…………… S.A.R. OF INH:  INH contains pyridine ring and hydrazine side chain.  The N-1 nitrogen in hydrazine side chain should be unsubstituted.  N-2 nitrogen can be substituted with alkyl groups to active compounds.  Repalcement of pyridine nucleus with other aromatic ring such as benzene, pipiridne or thiazole ring diminished the anti- tubercular activity.  If hydrazide substitution is shifted to position 2 or 3 instead of 4 then the compound is less active. R  If hydrazide group is replaced totally by alkyl or aryl group then the compound remains active but less than INH. ANTITB DRUGS…………… 2. RIFAMPICIN  It is an antibiotic obtained from Streptomyces mediterrianei.  It inhibits DNA-dependent RNA polymerase of mycobacteria by forming a stable drug enzyme complex, leading to suppression of initiation of chain formation in RNA synthesis  This drug act as a bactericidal drug. ANTITB DRUGS…………… S.A.R. OF RIFAMPICIN  Intact macrocyclic molecule is required for antimycobacterial activity.  It is formed by substitution of [(4-methyl-1-piperazinyl)imino)methyl] at 3 rd position of in rifamycin. RIFAMYCIN RIFAMPICIN ANTITB DRUGS…………… RIFABUTIN (Semisynthetic refamycin) ANTITB DRUGS……………  Double bonds in macrocyclic ring should not be reduced, or opening of the macro ring results in compounds have decreased activity.  Free –OH groups should be present at C-1, 8, 21 and C-23 all lie in a plane and play a role in acting as binding groups for attachment to DDRP.  When –OH groups at C-21 and C-23 were completely removed or substituted the formation of derivatives are devoid of antimycrobial activity were obtained.  Activity of the compounds get diminished when the –OH group at C-21 and C-23 are acetylated.  The maintenance of drug activity relies on the presence of either –OH group or :C=O group both of which should be unsubstituted. ANTITB DRUGS…………… 3. PYRAZINAMIDE (PZA)  Pyrazinamide is a synthetic pyrazinoic acid amide derivative with bactericidal property.  PZA is an important component of multidrug therapy for tuberculosis. It is a prodrug that stops the growth of M. tuberculosis.  Its bactericidal action is dependent upon the presence of bacterial pyrazinamidase, which removes the amide group to produce active pyrazinoic acid.  Under acidic conditions of pH 5 to 6, the pyrazinoic acid that slowly leaks out converts to the protonated conjugate acid, which is thought to diffuse easily back into the bacilli and accumulate. The net effect is that more pyrazinoic acid accumulates inside the bacillus at acid pH than at neutral pH.  The accumulation of pyrazinoic acid was also suggested to disrupt membrane potential and interfere with energy production, necessary for survival of M. tuberculosis at site of infection. ANTITB DRUGS…………… S.A.R. OF PZA  PZA contains pyrazine ring in its structure.  It has amide group at C-2.  Substitution on the pyrazine ring or the use of alternate heterocyclic aromatic rings have given compounds with reduced activity.  Using QSAR a series of analogs have been prepared with improved biological activity. MARKETED PRODUCTS REFRENCES 1. Alagarsamy V (2010). Textbook of Medicinal Chemistry. India, DC: Elsevier. ISBN:978-81-312-3321-4. 2. https://images.app.goo.gl/LEJobzJMFw883BJaA 3. https://www.slideshare.net/DeepakKumarGupta2/ antitubercular-drug 4. Initial Studies of Electronic and Structural Characterization of Anti-Depressive Brexpiprazole - Scientific Figure on ResearchGate. Available from: https://www.researchgate.net/figure/Piperazine-and-Aryl- Group-major-ligands-of-Brexpiprazole_fig1_331590107 [accessed 18 Oct, 2020] 5. https://images.app.goo.gl/6KqL88HpJhox1iXQ6 THANK YOU