Sulfonamides-Quinolones-Nitrofurans PDF

Al-Zaytoonah University of Jordan Faculty of Pharmacy Medicinal Chemistry 3 Course #: 0201511 3 Credit Hours Rima Hajjo, MS, PhD [email protected] Dima Sabbah, MS, PhD [email protected] 2023-2024 Reema Abu Khalaf, MS, PhD [email protected] Course Outline 1) Antibacterial/Antimicr...

Al-Zaytoonah University of Jordan Faculty of Pharmacy Medicinal Chemistry 3 Course #: 0201511 3 Credit Hours Rima Hajjo, MS, PhD [email protected] Dima Sabbah, MS, PhD [email protected] 2023-2024 Reema Abu Khalaf, MS, PhD [email protected] Course Outline 1) Antibacterial/Antimicrobial Agents 2) Antibiotics 3) Antimycobacterial agents 4) Antifungal agents 5) Anti-parasitic agents 6) Antiviral agents 7) Anticancer agents 2023-2024 Al-Zaytoonah University of Jordan Faculty of Pharmacy MedChem 3 Course #: 0201511 3 Credit Hours Antimicrobial/Antibacterial Agents       Sulfonamides Quinolones Nitrofurans Methenamine Fosmycin Metronidazole 2023-2024 Book Foye’s Medicinal Chemistry Book 2023-2024 Introduction: Mechanisms of Antibacterial Agents Fostomycin Madigan and Martinko, 2006 2023-2024 (1) SULFONAMIDES: Background Synthetic Antibacterial Agents Broad spectrum Used Mainly for Urinary Tract Infections (UTIs) General Considerations: • First, Sulfonamides came into use in the mid 1930’s • Then Penicillins in the 40’s • Combination therapies in the 1970’s (Co-trimoxazole) • FLuoroquinolones in the 1990’s Therapeutic Indications: • Lower UTI’s – urethritis, cystitis, prostatitis • Upper UTI’s – Pyelonephritis 2023-2024 The Discovery of Sulfonamide Antibacterial Agents The first drug to successfully treat bacterial infections and the first of many sulfa drugs—forerunners of antibiotics. This achievement earned its creator a Nobel Prize. Azo bond confers prodrug qualities reductive cleavage of the azo bond p-aminobenzenesulfonic acid amide Antimetabolite “Azo compound” Prontosil rubrum and patented as Prontosil, is an azo dye, introduced in 1935 by Gerhard Domagk, Bayer, Germany. Inactive in vitro! Active in vivo. PABA Natural Bacterial Metabolite 2023-2024 Mechanism of Action: Sulfonamides Inhibit Microbial Biosynthetic Pathway of Tetrahydro folic Acid Synthesis 6-hydroxymethyl-7,8-dihydropterin-pyrophosphate Glutamic acid ‘THFA’ Sulfonamides are bacteriostatic THFA is required for DNA synthesis The basis of selective toxicity to bacteria: Bacteria need to synthesize THFA in vivo, while 2023-2024 humans rely on food and supplements for folic acid and don’t synthesize it in vivo. Structure Activity Relationships (SAR) Acidic O N4 H S N O H2N O H O S H C O N1 pKa = 10.4 N O Ar H2N H2N Sulfanilamide H PABA pKa = 6.5 Ar = pKa MIC H 10.4 128.0 5.0 2.15 6.0 0.8 6.52 0.9 H3 C SAR: CH3 N O Isoxazole CH3 1. N4 must be unsubstituted or capable of regenerating the free NH2 2. No substitution on the aromatic ring O N Isoxazole 3. Acidic proton on N1 N 4. Exchange of SO2NHR by CONHR reduces the antibacterial activity (because of decreased acidity of N1 proton) N Pyrimidine N N 5. The amine and sulphonamide groups have to be para to each other 6. The protonated form of the drug is more active as antibacterial 2023-2024 S 5.5 CH3 Thiadiazole --- Structure Toxicity Relationships Acidic O N4 H S N H2N O H O H C O N1 H2N Sulfanilamide pKa = 10.4 PABA pKa = 6.5 1. The N1 heterocyclic ring, which causes a type I hypersensitivity reaction (i.e., hypersensitivity side effects). 2. The N4 amino nitrogen causes either direct cytotoxicity or immunologic response (i.e., hypersensitivity side effects). 3. Sulfonamide antibiotics with high pKa values are more nephrotoxic due to crystalluria. 2023-2024 Pharmacokinetic Properties 1) Most sulfonamides are well absorbed orally, and they are widely distributed including to the CNS. 2) The concentrations in the kidney are the highest. Therefore, they are suitable for treating urinary tract infections (UTIs). 3) Lower solubility in the urine, most sulfonamides and their metabolites easily cause crystalluria, bloody urine, and kidney damage. 2023-2024 Main Problems Acidic proton Site of acetylation “Acidic proton allows salt formation” O S H 2N O 1) Inactivated by metabolism 2) low water solubility 3) Irritation by basic salts H Unionized Sulfonamide Low water solubility Precipitates in urine  crystalluria S 1) Metabolism N Ar O H 3C C NH 2) Salt formation H 2N O N Ar O O S O H N4 acetylation (aniline nitrogen) N Salt “Inactive metabolite” Ar 3) Irritation? Low water solubility Precipitates in urine  crystalluria OH H H Alkaline salt causes irritation N OH Diethanolamine “Sulfonamide sales prepared with diethanolamine are less painful/less irritation” Sodium Salts are very alkaline because Na+ is quite alkaline  irritation. Therefore, diethanolamine sulfonamide salts are nearly neutral (i.e., less irritation 2023-2024and used on ophthalmic preparations). Sulfmethoxazole: Used for UTI, bronchitis, and prostatitis Sulfacetamide: Topical, treatment of acne and other skin conditions 2023-2024 Classification of Sulfonamides and their Clinical Uses According to administration route and the degree of absorption through GI tract: O H O NH N Oral, Absorbable: N S S O N Well absorbed from GIT O N O H N H N and mainly used to treat Sulfadiazine Sulfadoxine Sulfamethoxazole general infections. On the basis of their half-lives, can be classified into short-, medium-, or longSulfisoxazole Sulfamethizole acting. Oral, Nonabsorbable: Poorly absorbed in intestinal tract and mainly used to treat gastrointestinal tract infections. Sulfasalazine 2 2 O Topical Skin and eye infections NH S O O H2N Silver sulfadiazine (Wounds, Burns) Sulfacetamide (Eye drops) (Lotion for acne treatment) 2023-2024 Mafenide/Sulfamylone (Burns) Spectrum of Activity Broad spectrum, used for infections caused by G+ and G- bacteria Mechanisms of Bacterial Resistance to Sulfonamides 1) Increased synthesis of PABA 2) Mutation in enzyme changing its structure to better distinguish between PABA and the drug. 3) Some bacteria are intrinsically resistant since they can uptake Folic acid from environment. Note: The use of sulfamethoxazole and other sulfonamides has been limited due to an increasing incidence of resistant organisms. Their main use has been restricted for the treatment of acute, uncomplicated urinary-tract infections, particularly those caused by E. coli. 2023-2024 Combination Therapy for UTIs Sulfonamide + Trimethoprim O H N N H 2N N O O O P P OH + O OH N CO2H Dihydropteroate Synthase H H 2N OH H N O O H 2N H O H N N H Glutamic acid H 2N N N o CO2H C N H N H H N Dihydropteroic Acid N Sulfonamide H N H S O N N H 2N PABA PABA Dihydropteroate diphosphate CO2H O O CO2H Dihydrofolate reductase H H 2N H N N N CO2H C N N H H N CO2H H Dihydrofolic Acid Tetrahydrofolic Acid Trimethoprim 2023-2024 Trimethoprim Site of action of trimethoprim Antimetabolite 2023-2024 2023-2024 Repetitive Useful Slide Al-Zaytoonah University of Jordan Faculty of Pharmacy MedChem 3 Course #: 0201511 3 Credit Hours (2) Quinolone/Fluoroquinolone Antibacterial Agents 2023-2024 Quinolones: Background Ring 2 Ring 1 Nalidixic acid      Broad spectrum antibacterial. Used for UTIs. Were developed/used as antibacterial agents in the 60s. For the treatment of hospital-acquired pneumonia Nalidixic acid, the first discovered quinolone antibacterial, not in clinical use anymore. Now, nearly all quinolone drugs in clinical use are fluoroquinolones.  Due to increased concerns about toxicities and side effects, the FDA issued black box warnings in 2008, 2016, 2018. “Tendon damage”.  Musculoskeletal adverse effects, tendon rupture, colitis, CNS side effects (due to blockade of the GABAa receptor). 2023-2024 Example on black box warning for other drugs General Structure and Pharmacophore 5 4 3 6 7 Spectrum of activity 2 8 1 Atom number 8 used to be N, then changed to C to reduce side effects. Most quinolone drugs in clinical use have C at position 8. 2023-2024 Mechanism of action of Quinolones  Quinolones inhibit bacterial topoisomerase enzymes, resulting in inhibition of replication and transcription.  Inhibition of DNA gyrase in G- (also called topoisomerase II in G-) and topoisomerase IV in G+, which are key bacterial enzymes that dictate the conformation of DNA  that’s why the quinolones are rapidly bactericidal. 2023-2024 First Generation Quinolones 4 3 2 1 Oxolinic Acid “A naphthyridone”  Nalidixic acid was the first quinolone introduced to clinic in 1962 to fight against Gram negative urinary tract infections (UTIs)  it is considered a firstgeneration quinolone based on its spectrum of activity and pharmacokinetic properties. It is discontinued.  First-generation agents are limited to uncomplicated urinary tract infections. And they have problems with toxicity, antibacterial spectrum, and metabolism. 2023-2024 Second Generation Quinolones Broader spectrum against Gram Negative Longer half life Less protein binding when X = CH 2023-2024 Third Generation Quinolones The third-generation quinolones include levofloxacin, gatifloxacin, and gemifloxacin. 2023-2024 It is 4th generation in some references Fourth Generation Quinolones Trovafloxacin The first chlorinated fluoroquinolone developed. Removed from clinical use in 1999 Hepatotoxic 2023-2024 Summary Generation First Agents Antimicrobial Spectrum Properties Nalidixic acid Cinoxacin Gram negative Second Norfloxacin Lomefloxacin Enoxacin Ofloxacin Ciporfloxacin Gram negative (including Pseudomonas), Some Gram positive Adequate serum and tissue concentrations. Good for systemic infections. Third Levofloxacin Sparfloxacin Gatifloxacin Moxifloxacin Same as for secondgen. generation plus expanded Gram positive Once-daily dosing Fourth Trovafloxacin Besifloxacin Same as for thirdgen. plus broad anaerobic coverage Active against anaerobic Grampositive and negative (not Pseudomonas) 2023-2024 Poor serum and tissue concentration. Not for systemic infections General Structure and SAR Ring 2 Ring 1 2023-2024 SAR of Quinolones: Rings 1,4-dihydro-4-oxo-3-pyridinecarboxylic necessary for the antibacterial activity. acid portion is The pyridone ring (ring 1) must be attached to an aromatic ring (ring 2), in which isosteric substitution of carbon with nitrogen maintains the activity. O O 4 3 5 5 COOH N1 2 8 R Substituted 1,4-dihydro-4-oxo3-pyridinecarboxylic acid Ring 1 7 2 COOH 3 6 Ring 2 6 4 N 1 R Substituted quinolone 3-carboxylic acid 2023-2024 SAR: Isosteric substitutions on ring 2 Isosteric substitution of carbon with nitrogen maintains the antibacterial activity. O O 5 5 4 6 7 COOH 3 6 Ring 2 Ring 1 N 4 1 2 N 8 1,5-Naphthyridines Cinnolines O O 5 4 COOH 3 6N 7 8 COOH 3 7 2 N 1 8 N 1 R R 1,6-Naphthyridines 4 6 2 N 1 R R 5 COOH 3 7 N2 8 N 2023-2024 1,8-Naphthyridines SAR: N1 alkyl substitutions N1-Substitution is necessary for the antibacterial activity. Small alkyl or cycloalkyl groups increase the antibacterial activity in the following order: cyclopropyl >ethyl >methyl. O O 5 F 4 COOH 3 6 N 5 F 4 COOH 3 6 2 7 8 N N 1 2 7 8 N 1 HN HN Ciprofloxacin Norfloxacin 2023-2024 CH3 SAR: N1 aryl substitutions N1- Aryl substitution maintains the activity and sometimes optimises it. O 5 F 4 COOH 3 6 N 2 7 8 N F F H2N Trovafloxacin 2023-2024 1 F SAR: Substitutions on C2, C5, C6, C7 & C8  Substitution at C2 position decreases the activity remarkably or changes the antibacterial characters.  Substitution at C5 , C6 , C7 and at C8 has good effects on the activity.  C6 fluorine substitution increases the activity prominently, That’s why quinolones are also called fluoroquinolones.  Substituted or unsubstituted piperazinyl or pyrrolidinyl groups at C7 increase the activity against P. aeroginosa (spectrum of activity) O 5 4 COOH 3 6 7 2 8 N 1 R 2023-2024 Sparfloxacin SAR: New ring (ring fusion) from N1 to C8 Ring fusion at N1and C8; C5 and C6; C6 and C7 or C7 and C8 introduces active compounds: Examples: O 5 F O 4 COOH 3 5 H3CN 3 O 6 N 4 6 2 7 8 N O 1 X2 7 8 N1 O CH3 CH3 H Ofloxacin Levofloxacin (-)S X: N = Cinoxacin X: CH = Oxolinic acid 2023-2024 COOH SAR: Amino Acid Substitutions O H3C O O NH H NH2 H H3C N O H F N CO2H N F H N N H2N F CO2H N N F H H F F Alatrofloxacin Trovafloxacin Prodrug Alanines in alatrofloxacin are introduced to improve drug transportation into cell/improve absorption. 2023-2024 Removed from clinical use in 1999 Hepatotoxic Important Structural Modifications Quinolones were of little clinical significance until the addition of a fluoro group to C6 greatly increased the biologic activity  it improved cell wall penetration. A piperazinyl ring at position 7, was also beneficial for a variety of pharmacokinetic reasons due to the ability of the basic substituent to form a zwitterion with the carboxylic acid group at position 3. This property appears to radically enhance the ability of these compounds to penetrate the outer membrane of Gram negative bacteria. 2023-2024  The most active of the fluoroquinolones against Gram-negative bacteria.  A cyclopropyl substituent at position 1 further increased spectrum of activity.  Replacement of the nitrogen at position 8 with carbon reduced adverse reactions and increased activity against S. aureus. SAR of Toxicity and Side Effects Associated with CytP450 interactions Can J Infect Dis. 2002 Jan;13(1):5461. 2023-2024 SAR of Toxicity: CNS Toxicity  Unlike many anti-infective drugs, the quinolones can cause severe CNS effects even after short-term use.  CNS side effects include: Tremor, sleep disorders, anxiety, and convulsions because they cause GABA antagonism at the receptor.  Because of low penetration to brain this toxicity is rare. Flumequine (first generation) Causes severe CNS side effects 2023-2024 SAR of Side Events: Metal Chelation A problem of chemical incompatibility of all Quinolones with metal ions Metal chelate Molecules. 2013 Sep; 18(9): 11153–11197.  The ability of these drugs to chelate polyvalent metal ions (Ca2+ , Mg2+ , Zn2+ , Fe2+, Al3+ ), resulting in decreased solubility and reduced drug absorption.  Causes kidney caliculi and crystalluria. (advice patients to drink lots of water)  Chelation occurs between the metal and the 3-carboxylic acid and 4-keto groups.  Agents containing polyvalent metals should be administered separately from the quinolones. 2023-2024 Metabolism of Quinolones Critical for binding COOH O Cell penetration Gyrase inhibition F N Phase 2 Conjugation O O OH O O C F HO OH OH N R1 O Pharmacophore N Inactive Phase 1 CYP 450 (1A2) R1 Potency O Improves activity against a variety of organisms (Spectrum of activity) F HO R2 N N COOH N R1 Reduced activity 2023-2024 R Al-Zaytoonah University of Jordan Faculty of Pharmacy MedChem 3 Course #: 0201511 3 Credit Hours (3) Nitrofurans and Other Antimicrobial Agents 2023-2024 Nitroheteroaromatic compounds: 1) High toxicity but little acquired resistance.  Widely used as oral antibacterial since WWII. It is used for prophylaxis or treatment of acute urinary tract infections when kidney function is NOT impaired.  Nausea and vomiting are common side effects. Severe side effects can occur such as acute pulmonary reactions, peripheral neuropathy, hemolytic anemia, liver toxicity, and fertility impairment.  Inhibits DNA and RNA functions through unknown mechanisms. 2) Important Antiparasitic agent.  Used orally for treating trichomoniasis, giardiasis, and Gardnerella vaginalis infections.  Used parenterally to treat anaerobic infections and pseudomembranous colitis due to Clostridium difficile (opportunistic pathogen that occasionally flourishes as a consequence of broad-spectrum antibiotic therapy, and infections can be lifethreatening).  It is believed to be metabolically activated by reduction of its nitro group to produce metabolites that interfere with DNA and RNA function. More on nitrofurans Nitrofurans For UTIs For the management of chronic prostatitis. O O O O2N C N H O NH N O2N O C N H N O Extended conjugation of electrons (Brown Color  urine discoloration) Nitrofurantoin Furazolidone Metabolism O2N O C X H Can cause hepatic injury (Hepatic drug reactions are more common in females for unknown reasons). O H HO N NH O C N H N O Active form O H H N NH O C N H N O 2023-2024 Other examples: acetaminophen, halothane, nitrofurantoin, diclofenac, and sulindac. Synthesis of Nitrofurantoin O2N O C X H SAR: O 2N O furan R O 2N S thiophene R O2N NH R pyrrole  Replacing the furan ring with other five-membered rings such as thiophene and pyrrole are less active).  Replacing nitro with other isolelectric groups (e.g., sulfo, sulfamoyl, carboxyl or cyano) reduce the antibacterial activity. 2023-2024 Methenamine (Hexamethylenetetramine) For UTIs Acidic media (Hexamine) Can form Schiff base with protein H Protein N C H Schiff base (imine) 2023-2024 Fosfomycin For UTIs  Fosfomycin (also known as phosphomycin) inhibits enolpyruvial transferase, an enzyme catalyzing an early step in bacterial cell wall biosynthesis. Inhibition results in reduced synthesis of peptidoglycan, an important component in the bacterial cell wall.  Fosfomycin is bactericidal against Escherichia coli and Enterobacter faecalis infections.  It is used for treatment of uncomplicated urinary tract infections by susceptible organisms. 2023-2024 Phenazopyridine For UTIs UTI Analgesic (does not have antibacterial properties) N N H2N N NH2 Azo dye bright red in color Urinary analgesic – does not heal infections 2023-2024