Medicinal Chemistry Introduction PDF

Medicinal Chemistry Introduction CH456 Medicinal Chemistry © 2025 James H. Gerlach The Five Deadliest Infectious Diseases (Highest Case Fatality Rates) 1. Rabies (essentially 100%) 2. Ebola haemorrhagic fever (83%) 3. Marburg haemorrhagic fever (80%) 4. H5N1 avian influ...

Medicinal Chemistry Introduction CH456 Medicinal Chemistry © 2025 James H. Gerlach The Five Deadliest Infectious Diseases (Highest Case Fatality Rates) 1. Rabies (essentially 100%) 2. Ebola haemorrhagic fever (83%) 3. Marburg haemorrhagic fever (80%) 4. H5N1 avian influenza (~60%) 5. Nipah virus (40% to 70%) Global Trends in the Estimated Number of TB deaths (left) and the Mortality Rate (right) for 2000–2020 The Deadliest and Most Communicable Diseases Malaria Is the Disease Responsible Historically for the Most Worldwide Deaths Malaria is a life-threatening disease caused by parasites that are transmitted to people through the bites of infected female Anopheles mosquitoes. It is preventable and curable. In 2023, there were an estimated 263 million cases of malaria worldwide. An increase of 11 million cases from the previous year. The estimated number of malaria deaths stood at 597,000 in 2023. The WHO African Region carries a disproportionately high share of the global malaria burden. In 2023, the region was home to 94% of malaria cases and 95% of malaria deaths. Children under 5 accounted for 76% of deaths in the Region, compared with 91% in 2000. Countries with Indigenous Cases of Malaria in 2000 and Their Status by 2023 True Size of Africa Quinine Cinchona bark Cinchona is a genus of about 38 species in the family Rubiaceae, native to tropical South America. The bark of the tree is medicinally active containing a variety of alkaloids including: Quinine, which interferes with the reproduction of malaria-causing protozoa, and Quinidine, which is an antiarrhythmic. According to legend, the first European ever to be cured from malaria fever was the wife of the Spanish Viceroy of Peru, the countess of Chinchón. The Peruvian bark was brought to Europe in the 1640s. In 1753, Carolus Linnaeus named the bark Cinchona after the countess of Chinchón. Homeopathy and Cinchona Birth of homeopathy was based on Cinchona bark testing. Dr. Samuel Hahnemann He was the founder of homeopathy in 1796. Conceived of homeopathy while translating Cullen's Materia medica (1789). Peruvian bark was known to cure intermittent fevers (i.e., malaria). Hahnemann took large doses of Peruvian bark daily. After two weeks, he said he felt malaria-like symptoms. His idea of "like cures like" was the starting point of his writings on Homeopathy. Hahnemann's symptoms are now believed to be the result of a hypersensitivity he had to the Cinchona bark. Discovery of the Malaria Parasite Alphonse Laveran (Born in Paris in 1845) He became a military doctor. At age 29 he was appointed professor of military diseases and epidemics at the School of Military Medicine of Val- de-Grâce in Paris. In 1878, he was posted in Algeria. There, he studied blood and organs of infected patients and discovered a motile parasite. He was awarded a Nobel Prize in 1907. Quinine Quinine Natural, white crystalline alkaloid Antimalarial Analgesic Antipyretic Anti-inflammatory Bitter taste Gin and tonic Quinine Total Synthesis Total synthesis of quinine Efforts over 150 years represents a milestone in organic chemistry. 1817 – Pierre Joseph Pelletier and Joseph Caventou isolate quinine from cinchona tree. 1853 – Louis Pasteur produces quinotoxine by acid- catalyzed isomerisation of quinine. Quinine Total Synthesis 1856 – William Henry Perkin attempts quinine synthesis by oxidation of N-allyl toluidine. Idea was that 2 equivalents of N-allyl toluidine (C10H13N) plus 3 equivalents of oxygen (O) would yield one equivalent of C20H24N2O2 (quinine's chemical formula) and one equivalent of water. 1907 – Paul Rabe establishes correct atom connectivity. Quinine Total Synthesis 1918 – Paul Rabe and Karl Kindler synthesize quinine from quinotoxine, reversing the Pasteur chemistry. Quinotoxine to quinidinone Quinine Total Synthesis 1918 – Rabe and Kindler synthesize quinine from quinidinone. Lack of experimental details becomes a major issue in the Stork/Woodward controversy almost a century later. Quinidinone to quinine + diastereomers Quinine Total Synthesis 1939 – Rabe and Kindler reinvestigate a sample left over from their 1918 experiments and identify and isolate quinine (again) together with diastereomers quinidine, epi-quinine and epi-quinidine. 1944 – Bob Woodward and W.E. Doering report the total synthesis of quinine starting from 7-hydroxyisoquinoline. Not the synthesis of quinine, but that of the precursor homomeroquinene (racemic) and then quinotoxine (enantiopure after chiral resolution). Argue that Rabe in 1918 already proved that this compound will eventually give quinine, but do not repeat Rabe's work. Quinine Total Synthesis 1944 – 22-year-old Gilbert Stork writes to Woodward asking him if he had repeated Rabe's work. 1945 – Woodward and Doering publish their second lengthy quinine paper. 1974 – Kondo and Mori synthesize racemic vinylic gamma-lactones, a key starting material in Stork’s 2001 quinine synthesis. 1988 – Ishibashi & Taniguchy resolve racemic lactones to enantiopure compounds via chiral resolution. Woodward–Doering Quinine Synthesis Quinine Total Synthesis 2001 – Gilbert Stork publishes his stereoselective quinine synthesis. Questions the validity of the Woodward/Doering claim: "the basis of their characterization of Rabe’s claim as ‘established’ is unclear”. 2007 – Jeffrey Seeman concludes in a 36-page review that the Woodward–Doering/Rabe–Kindler total synthesis of quinine is valid. Writes in conclusion: “In all these issues, good science requires adhering to the highest of standards—a fine lesson for all of us, whatever level of achievement we may have already reached in our profession.” 2008 – Smith and Williams revisit and confirm Rabe's D‑quinotoxine to quinine route. Stork Stereoselective Quinine Synthesis Related Antimalarial Drugs Chloroquine (1934) Amodiaquine (1948) Paracetamol (Acetaminophen) What’s in a name? IUPAC name N-(4-hydroxyphenyl)-acetamide Other chemical names N-acetyl-para-aminophenol, APAP, para-acetamidophenol International Nonproprietary Name (INN) Paracetamol What’s in a name? British Approved Name (BAN) Paracetamol United States Adopted Name (USAN) Acetaminophen Proprietary names Tylenol, Panadol, Panamax, Perdolan, Calpol, Doliprane, Tachipirina, Atasol, Ben-u-ron and others What’s the origin of these names? Paracetamol para-acetylaminophenol Acetaminophen para-acetylaminophenol Tylenol® para-acetylaminophenol APAP N-acetyl-para-aminophenol Julius Axelrod and Bernard Brodie Demonstrated Acetanilide is Metabolized to Paracetamol in 1948 Acetanilide 1886 Antipyretic and analgesic Methaemoglobinemia was a serious side effect. High levels of metHb in the blood leads to liver and kidney damage. Analgesic effect identified 1948 Julius Acetanilide metabolized in Axelrod the body to paracetamol. McNeil Laboratories 1955 Tylenol Children's Elixir Paracetamol Total Synthesis 1. Phenol is nitrated with dilute H2SO4 and NaNO3. 2. Para isomer separated from ortho isomer by fractional distillation. 3. 4-nitrophenol is reduced to 4-aminophenol with NaBH4. 4. 4-aminophenol is reacted with acetic anhydride. Paracetamol Mechanism of Action Paracetamol acts via at least two pathways. Cyclooxygenase (COX) family of enzymes Paracetamol reduces the oxidized form of the COX enzyme in the brain, which may contribute to its ability to treat fever and pain. May act by inhibiting the COX-3 isozyme. Paracetamol is metabolized in the body to AM404 AM404 may inhibit uptake of the endogenous cannabinoid anandamide by neurons, preventing activation of pain receptors (nociceptors). AM404 may inhibit sodium channels in a manner similar to that of local anaesthetics such as lidocaine and procaine. Anandamide AM404 Paracetamol Metabolism Metabolised primarily in the liver Major metabolites are inactive sulfate and glucuronide conjugates, which are excreted by the kidneys. Minor metabolites are metabolised via the hepatic cytochrome P450 enzyme system. CYP2E1 and CYP1A2 isoenzymes Alkylating metabolite: N-acetyl-p-benzo-quinone imine (NAPQI) NAPQI toxicity Normally produced only in small amounts. Usually detoxified quickly by combining irreversibly with the sulfhydryl groups of glutathione. Pathway becomes saturated during overdose. Reactions Involved in Paracetamol Metabolism NAPQI Toxicity (Mitochondrial Permeability Transition Pore) Treating Paracetamol Overdoses Dosage Toxic dose varies between 4g to 6g. Lethal dose varies between 10g to 15g. Lowered by concomitant alcohol consumption. Treatment Acetylcysteine administered within 8 hours offers the best prognosis. Acetylcysteine replenishes the liver's supply of glutathione. Without treatment Symptoms of liver failure typically appear 16 to 36 hours after the initial overdose. Death occurs due to acute liver failure.