B Pharmacy Sem 6: Medicinal Chemistry III

Subject  1. Medicinal Chemistry III

Unit 1 – Antibiotics (β‑Lactams, Aminoglycosides, Tetracyclines)

Unit 2 – Antibiotics & Antimalarials (Macrolides, Chloramphenicol, Prodrugs, Quinolines, Biguanides)

Unit 3 – Anti‑tubercular, Urinary Tract Agents, Antivirals

Unit 4 – Antifungals, Antiprotozoals, Anthelmintics, Sulfonamides/Sulfones

Unit 5 – Drug Design Basics & Combinatorial Chemistry

Unit 1: Antibiotics (β‑Lactams, Aminoglycosides, Tetracyclines)

This unit covers three major classes of antibacterial agents with diverse mechanisms of action, structural frameworks, and therapeutic applications. Focus is placed on their structure–activity relationships (SAR), mechanisms of resistance, clinical utility, and adverse effects.

1.1 β‑Lactam Antibiotics

These are the most widely used antibiotics. They contain a β‑lactam ring, crucial for antibacterial activity by inhibiting bacterial cell wall synthesis.

1.1.1 Penicillins

• Mechanism: Inhibit transpeptidase (PBP) enzymes → block peptidoglycan cross-linking → bacterial lysis (mainly Gram‑positive).

• SAR:

  • β‑lactam ring (essential)

  • Thiazolidine ring + side chain (defines spectrum)

  • Electron-withdrawing groups on side chain → ↑ acid stability (e.g., ampicillin)

• Examples:

  • Penicillin G/V (natural)

  • Ampicillin, Amoxicillin (broad-spectrum)

  • Cloxacillin, Oxacillin (β‑lactamase-resistant)

• Resistance Mechanisms:

  • β‑lactamase enzymes (hydrolyze β‑lactam ring)

  • Altered PBPs (e.g., MRSA)

• Side Effects: Allergic reactions, rash, diarrhea

1.1.2 Cephalosporins

• Mechanism: Similar to penicillins; broader spectrum.

• Classification:

  • 1st Gen: Cefazolin, Cephalexin – Gram-positive

  • 2nd Gen: Cefuroxime – more Gram-negative

  • 3rd Gen: Ceftriaxone, Ceftazidime – crosses BBB, serious Gram-negative

  • 4th Gen: Cefepime – resistant to β‑lactamase

  • 5th Gen: Ceftaroline – active against MRSA

• SAR:

  • Dihydrothiazine ring + β‑lactam

  • Substituents at C7 (activity), C3 (PK/PD)

• Resistance: β‑lactamases, efflux pumps

• Side Effects: Cross-allergy with penicillins, GI upset

1.1.3 Carbapenems & Monobactams

• Imipenem, Meropenem (carbapenems) – broadest spectrum

• Aztreonam (monobactam) – Gram-negative only, safe in penicillin allergy

1.2 Aminoglycosides

Bactericidal agents that inhibit protein synthesis by binding to 30S ribosomal subunit, causing misreading of mRNA.

• Examples: Streptomycin, Gentamicin, Amikacin, Tobramycin

• SAR:

  • Aminocyclitol ring (essential)

  • Multiple amino sugars (polycationic → poor oral absorption)

• Mechanism: Disrupt initiation complex & misreading → faulty proteins → membrane damage

• Spectrum: Aerobic Gram-negative bacilli; synergistic with β‑lactams for Gram-positives

• Resistance:

  • Enzymatic inactivation (acetylation, phosphorylation, adenylation)

  • Efflux pumps

  • Ribosomal mutation

• Adverse Effects:

  • Nephrotoxicity (renal proximal tubules)

  • Ototoxicity (vestibular/cochlear)

  • Neuromuscular blockade

1.3 Tetracyclines

Broad-spectrum, bacteriostatic agents that inhibit protein synthesis by binding the 30S ribosomal subunit, preventing tRNA binding.

• Examples: Tetracycline, Doxycycline, Minocycline

• SAR:

  • Four fused hydrocarbon rings (tetracyclic nucleus)

  • Modification at C5–C9 alters potency and PK

• Mechanism: Reversible inhibition of aminoacyl‑tRNA binding to the A-site

• Spectrum: Gram-positive, Gram-negative, intracellular organisms (Chlamydia, Rickettsia)

• Resistance:

  • Efflux pumps

  • Ribosomal protection proteins

  • Enzymatic inactivation

• Adverse Effects:

  • GI irritation, photosensitivity

  • Tooth discoloration (contraindicated in children/pregnancy)

  • Fanconi syndrome (expired tetracycline)

Key Exam Highlights

• Compare β‑lactam classes based on ring structure and resistance to β‑lactamases.

• Aminoglycoside toxicity profiles are classic – remember nephro‑oto risk.

• Tetracyclines are key for intracellular pathogens but have notable side effects (teeth, GI).

• SARs and mechanism of resistance are frequently asked in university exams and GPAT.

Unit 2: Antibiotics & Antimalarials (Macrolides, Chloramphenicol, Prodrugs, Quinolines, Biguanides)

This unit explores additional classes of antibiotics along with key antimalarial agents, focusing on their mechanism of action, structure–activity relationships (SAR), clinical use, resistance, and adverse effects. Emphasis is placed on protein synthesis inhibitors, DNA-damaging drugs, and antiprotozoal mechanisms.

2.1 Macrolide Antibiotics

Macrolides are bacteriostatic agents that inhibit bacterial protein synthesis by binding to the 50S ribosomal subunit, blocking translocation.

• Examples: Erythromycin, Azithromycin, Clarithromycin

• Structure: Large lactone ring (14–16 membered) + deoxy sugar (desosamine)

• SAR Highlights:

  • Lactone ring essential for activity

  • Hydroxyl and methyl groups influence acid stability and spectrum

  • Substitutions at C6, C9 improve PK properties (e.g., azithromycin)

• Mechanism: Prevent movement of ribosome along mRNA

• Spectrum: Gram-positive cocci, atypicals (Mycoplasma, Chlamydia, Legionella)

• Resistance:

  • Methylation of 23S rRNA

  • Efflux pumps

• Adverse Effects:

  • GI upset (erythromycin → motilin receptor agonist)

  • QT prolongation

  • CYP3A4 inhibition (notable for erythro-, clarithromycin)

2.2 Chloramphenicol

A broad-spectrum antibiotic with serious toxicity risks, used selectively.

• Mechanism: Binds 50S ribosomal subunit → inhibits peptidyl transferase activity → halts protein chain elongation

• Structure: Nitrobenzene ring + dichloroacetyl group

• Spectrum: Broad – Gram-positive, Gram-negative, anaerobes

• Resistance:

  • Enzymatic inactivation by chloramphenicol acetyltransferase (CAT)

• Adverse Effects:

  • Aplastic anemia (dose-independent)

  • Gray baby syndrome (immature glucuronidation)

  • Bone marrow suppression (reversible)

2.3 Prodrugs in Antibacterial/Antiparasitic Therapy

Prodrugs are inactive forms converted in vivo to active agents via enzymatic/chemical transformation.

• Examples:

  • Isoniazid: activated by mycobacterial KatG enzyme → inhibits mycolic acid synthesis

  • Metronidazole: reduced in anaerobic organisms → generates reactive intermediates that damage DNA

  • Nitrofurantoin: reduced by bacterial nitroreductases → reactive radicals → DNA damage

• Importance:

  • Improve bioavailability, selectivity, and safety

  • Bypass resistance or site-specific activation

2.4 Quinolines (Antimalarials)

Quinolines are synthetic antimalarials that interfere with heme metabolism in Plasmodium parasites.

2.4.1 4-Aminoquinolines

• Example: Chloroquine

• Mechanism: Accumulates in parasite food vacuole → inhibits heme polymerase → toxic heme buildup

• SAR:

  • Quinoline core (essential)

  • Side chain determines potency/resistance

• Resistance: PfCRT gene mutations → reduced accumulation in food vacuole

• Adverse Effects: Retinopathy, GI upset

2.4.2 8-Aminoquinolines

• Example: Primaquine

• Mechanism: Generates ROS → disrupts mitochondrial function; effective against liver hypnozoites (P. vivax, P. ovale)

• Caution: G6PD deficiency → hemolysis

2.4.3 Other Derivatives

• Mefloquine: effective for resistant strains

• Amodiaquine: similar to chloroquine

• Lumefantrine: used in combination with artemether

2.5 Biguanides (Antimalarials)

Biguanides interfere with folate synthesis, essential for DNA replication in Plasmodium.

• Examples: Proguanil, Cycloguanil

• Mechanism:

  • Proguanil → metabolized to cycloguanil (active form)

  • Inhibits Plasmodium dihydrofolate reductase (DHFR)

• Use: Often in combination (e.g., atovaquone/proguanil aka Malarone)

• Resistance: DHFR mutations

Key Exam Tips

• Macrolide mechanism: Think “macroslides” → block ribosome sliding.

• Chloramphenicol toxicity is a favorite viva topic – know aplastic anemia vs gray baby.

• Prodrug activation and why it’s used — classic concept questions.

• Chloroquine SAR and resistance via heme detox pathways.

• Biguanides are often overlooked — highlight their folate-targeting action.

Unit 3: Anti-Tubercular Drugs, Urinary Tract Agents, Antivirals

This unit covers drugs used in tuberculosis (TB), urinary tract infections (UTIs), and viral diseases. The focus is on mechanisms of action, structure–activity relationships (SAR), resistance patterns, and key clinical uses.

3.1 Anti-Tubercular Drugs

Drugs used to treat tuberculosis, caused by Mycobacterium tuberculosis. Therapy usually involves multiple drugs over a long duration to prevent resistance.

First-Line Drugs (RIPE Therapy)

1. Rifampicin (R)

• Mechanism: Inhibits DNA-dependent RNA polymerase → blocks RNA synthesis

• SAR: Naphthalene ring with ansa chain (macrocyclic)

• Use: Bactericidal; key in combination therapy

• Side Effects: Hepatotoxicity, orange-red discoloration of body fluids, enzyme inducer

2. Isoniazid (I)

• Mechanism: Prodrug activated by bacterial KatG → inhibits mycolic acid synthesis (cell wall)

• SAR: Hydrazide group is essential

• Resistance: KatG mutation

• Side Effects: Hepatotoxicity, peripheral neuropathy (prevent with vitamin B6)

3. Pyrazinamide (P)

• Mechanism: Prodrug → converted to pyrazinoic acid → disrupts membrane potential

• Use: Sterilizing agent (active in acidic pH)

• Side Effects: Hepatotoxicity, hyperuricemia

4. Ethambutol (E)

• Mechanism: Inhibits arabinosyl transferase → blocks arabinogalactan synthesis (cell wall)

• Side Effects: Optic neuritis (color blindness)

Second-Line Drugs

• Examples: Streptomycin, Capreomycin, Ethionamide, PAS (para-aminosalicylic acid)

• Used in drug-resistant TB or intolerance to first-line agents

3.2 Urinary Tract Antibacterial Agents

Drugs used to treat infections of the urinary tract (kidneys, bladder, urethra). Most act locally in the urinary tract and have minimal systemic effects.

1. Nitrofurantoin

• Mechanism: Reduced by bacterial enzymes → reactive intermediates → damage DNA/proteins

• Use: Acute uncomplicated cystitis

• Notes: Safe in pregnancy (except near term), concentrates in urine

• Side Effects: GI upset, pulmonary fibrosis (long-term)

2. Methenamine

• Mechanism: Converts to formaldehyde in acidic urine → nonspecific bactericidal effect

• Use: Chronic UTI prophylaxis

• Important: Not used in renal insufficiency

3. Fosfomycin

• Mechanism: Inhibits MurA enzyme → blocks cell wall synthesis (early step)

• Use: Single-dose treatment for uncomplicated UTIs

4. Sulfamethoxazole + Trimethoprim (Co-trimoxazole)

• Mechanism: Sequential inhibition of folate synthesis

  • SMX: inhibits dihydropteroate synthase

  • TMP: inhibits dihydrofolate reductase

• Use: Broad spectrum; used in UTIs, also in Pneumocystis pneumonia

• Side Effects: Allergies, rash, bone marrow suppression

3.3 Antiviral Drugs

Antiviral agents inhibit the replication cycle of viruses at various stages: entry, genome replication, or assembly.

1. Anti-Herpes Drugs

Acyclovir

• Mechanism: Guanine analog → activated by viral thymidine kinase → inhibits viral DNA polymerase → chain termination

• Use: HSV-1, HSV-2, VZV

• SAR: Acyclic sugar moiety replaces cyclic sugar

• Side Effects: Nephrotoxicity (IV form), CNS symptoms

Valacyclovir: Oral prodrug of acyclovir → better bioavailability

2. Anti-Influenza Drugs

Oseltamivir, Zanamivir

• Mechanism: Inhibit neuraminidase → prevents viral release

• Use: Influenza A and B

• Notes: Must be started within 48 hours of symptom onset

3. Anti-HIV Drugs (Overview)

Grouped by their targets in the HIV replication cycle.

a. NRTIs (Nucleoside Reverse Transcriptase Inhibitors)

• Examples: Zidovudine (AZT), Lamivudine

• Mechanism: Chain termination after incorporation into viral DNA

b. NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors)

• Examples: Nevirapine, Efavirenz

• Mechanism: Directly inhibit reverse transcriptase (non-competitive)

c. Protease Inhibitors (PIs)

• Examples: Ritonavir, Lopinavir

• Mechanism: Inhibit HIV protease → block protein processing

d. Integrase Inhibitors

• Example: Raltegravir

• Mechanism: Prevents integration of viral DNA into host genome

e. Entry Inhibitors

• Example: Enfuvirtide (fusion inhibitor), Maraviroc (CCR5 antagonist)

Key Exam Pointers

• RIPE therapy: Know each drug’s target & side effects.

• UTI drugs: Focus on local action and urine concentration.

• Acyclovir: Activated by viral enzyme → high selectivity.

• Oseltamivir: Prevents release, not entry.

• HIV drugs: Match class with target (reverse transcriptase, protease, integrase, entry).

Unit 4: Antifungals, Antiprotozoals, Anthelmintics, Sulfonamides/Sulfones

This unit introduces four diverse groups of anti-infective agents, focusing on their mechanisms of action, key structural features, clinical uses, and major adverse effects—all in a concise, student‑friendly format.

4.1 Antifungal Agents

Drugs that target fungal cell membranes or cell walls, exploiting differences from mammalian cells.

4.1.1 Polyenes

• Example: Amphotericin B

• Mechanism: Binds ergosterol → creates membrane pores → leakage of ions

• Use: Severe systemic mycoses (e.g., cryptococcal meningitis)

• Adverse Effects: Nephrotoxicity, infusion‑related fever/chills

4.1.2 Azoles

• Examples: Fluconazole, Itraconazole, Voriconazole

• Mechanism: Inhibit 14‑α‑demethylase → block ergosterol synthesis

• SAR: Imidazole/ triazole ring binds heme iron of CYP enzyme

• Use: Mucosal and systemic infections (e.g., candidiasis, cryptococcosis)

• Adverse Effects: Hepatotoxicity, drug–drug interactions (CYP inhibition)

4.1.3 Echinocandins

• Examples: Caspofungin, Micafungin

• Mechanism: Inhibit β‑(1,3)‑glucan synthase → weaken cell wall

• Use: Invasive candidiasis, aspergillosis salvage therapy

• Adverse Effects: Mild infusion reactions, hepatotoxicity

4.2 Antiprotozoal Agents

Drugs active against protozoan parasites (e.g., malaria, amoebiasis).

4.2.1 Nitroimidazoles

• Example: Metronidazole

• Mechanism: Reduction in anaerobes → reactive intermediates damage DNA

• Use: Amoebiasis, giardiasis, trichomoniasis

• Adverse Effects: Metallic taste, disulfiram‑like reaction with alcohol

4.2.2 Nitrofurans

• Example: Nifurtimox (Chagas disease)

• Mechanism: Generates free radicals → oxidative damage to parasite

• Use: Trypanosomiasis

• Adverse Effects: GI upset, neurological symptoms

4.3 Anthelmintic Agents

Drugs that eliminate parasitic worms by disrupting their neuromuscular function or metabolism.

4.3.1 Benzimidazoles

• Examples: Albendazole, Mebendazole

• Mechanism: Bind β‑tubulin → inhibit microtubule polymerization → impaired glucose uptake

• Use: Roundworms, hookworms, whipworms

• Adverse Effects: GI discomfort, headache

4.3.2 Nicotinic Agonist

• Example: Pyrantel pamoate

• Mechanism: Depolarizing neuromuscular blocker → spastic paralysis of worms

• Use: Pinworm, roundworm infections

• Adverse Effects: Mild GI upset, dizziness

4.3.3 Macrocyclic Lactones

• Example: Ivermectin

• Mechanism: Enhances GABA‑gated chloride channels → paralysis of parasite

• Use: Onchocerciasis, strongyloidiasis

• Adverse Effects: Mazzotti reaction (immune response to dying worms)

4.4 Sulfonamides & Sulfones

Structural analogs of PABA that block folate synthesis in bacteria and some protozoa.

4.4.1 Sulfonamides

• Example: Sulfamethoxazole

• Mechanism: Competitive inhibition of dihydropteroate synthase → ↓ dihydrofolate

• Use: UTIs, Nocardia infections (often with TMP as co-trimoxazole)

• Adverse Effects: Hypersensitivity (Stevens–Johnson), kernicterus in neonates

4.4.2 Sulfones

• Example: Dapsone

• Mechanism: Similar to sulfonamides; also anti‑inflammatory in skin

• Use: Leprosy, dermatitis herpetiformis

• Adverse Effects: Hemolysis (G6PD deficiency), methemoglobinemia

Key Exam Tips

• Antifungals: Remember “polyene = pores,” “azole = ergosterol synthesis,” “echinocandin = cell wall.”

• Antiprotozoals: Nitro group → DNA damage; watch for alcohol interaction with metronidazole.

• Anthelmintics: Benzimidazoles block tubulin; ivermectin targets GABA channels.

• Sulfonamides vs. Sulfones: Both inhibit folate but sulfones (dapsone) treat leprosy with notable hematologic toxicity.

Unit 5: Drug Design Basics & Combinatorial Chemistry

This unit introduces the principles of rational drug design, quantitative structure–activity relationships (QSAR), pharmacophore modeling, and the strategies of combinatorial chemistry to generate and screen large compound libraries efficiently.

5.1 Principles of Rational Drug Design

Designing molecules based on knowledge of biological targets and ligand–receptor interactions.

• Target Identification & Validation

  • Choose a protein or receptor critical in disease.

  • Verify its role via genetics, cell assays, or animal models.

• Lead Discovery

  • High‑throughput screening (HTS): Test thousands of compounds against the target.

  • Fragment‑based design: Screen small “fragment” molecules and grow them into potent leads.

• Lead Optimization

  • SAR studies: Systematically modify functional groups to improve potency, selectivity, and ADME.

  • Lipinski’s Rule of Five: Guide oral bioavailability (e.g., MW < 500, H‑bond donors ≤ 5).

5.2 Quantitative Structure–Activity Relationships (QSAR)

A mathematical approach correlating chemical structures with biological activity.

• Descriptors: Numerical values for lipophilicity (log P), electronic effects (Hammett σ), steric factors (Taft Es).

• Modeling: Use linear regression or machine‑learning to predict activity from descriptors.

• Validation: Training vs. test set; r² (fit) and q² (predictivity) metrics.

5.3 Pharmacophore Modeling

Abstract representation of the essential features required for biological activity.

• Key Features: Hydrogen‑bond donors/acceptors, hydrophobic centers, aromatic rings, ionizable groups.

• Alignment: Overlay active compounds to identify common pharmacophore.

• Virtual Screening: Search databases for molecules matching the pharmacophore.

5.4 Combinatorial Chemistry

Techniques to rapidly generate large libraries of structurally related compounds.

• Solid‑Phase Synthesis

  • Attach a scaffold to resin beads, perform iterative coupling and deprotection.

  • Advantages: Easy purification (wash away excess reagents).

• Split‑and‑Pool Method

  1. Divide resin into batches, couple different building block A in each.

  2. Pool, mix, then split again for coupling with block B, etc.

  • Generates n×m×… compounds in few steps.

• Diversity‑Oriented Synthesis (DOS)

  • Design routes that maximize structural diversity (skeletal and stereochemical).

  • Yields novel scaffolds beyond traditional “flat” libraries.

5.5 Library Screening & Lead Selection

• High‑Throughput Screening (HTS): Automated assays to test library against target.

• Affinity Selection‑Mass Spectrometry (AS‑MS): Detect binding without labeling.

• Hit-to‑Lead: Validate hits, assess potency, selectivity, and drug‑likeness.

Key Exam Tips

• Rational design flows: target → lead → optimize → candidate.

• QSAR: Remember common descriptors (log P, σ, Es) and the meaning of r² vs. q².

• Pharmacophore: It’s the “shape and features” map for binding.

• Combinatorial synthesis: Know solid-phase vs. split-and-pool basics.

• Screening methods: Differentiate HTS (volume) from AS‑MS (label‑free).