Infectious diseases such as tuberculosis, urinary tract infections, and viral illnesses continue to challenge global healthcare systems. Advances in medicinal chemistry have led to the development of highly specific drugs that target microbial survival pathways while minimizing harm to the host. Unit 3 examines anti-tubercular agents, urinary tract anti-infective drugs, and antiviral agents, emphasizing their chemical nature, structure–activity relationships (SAR), and therapeutic relevance.
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Anti-Tubercular Agents: Combating a Persistent Global Threat
Overview of Tuberculosis Chemotherapy
Tuberculosis (TB) is caused by Mycobacterium tuberculosis, an organism with a complex cell wall that demands prolonged and combination therapy. Anti-tubercular drugs are designed to inhibit mycolic acid synthesis, nucleic acid formation, or protein synthesis, thereby preventing bacterial survival and resistance development.
Synthetic Anti-Tubercular Agents
Isoniazid
Isoniazid is a first-line synthetic anti-tubercular drug and a cornerstone of TB therapy. Chemically, it is a hydrazide derivative that inhibits mycolic acid synthesis, essential for mycobacterial cell wall integrity. Its SAR highlights the importance of the hydrazine moiety for activity. Isoniazid undergoes chemical degradation through hydrolysis, and genetic variation in acetylation affects patient response and toxicity.
Ethionamide and Ethambutol
Ethionamide, structurally related to isoniazid, interferes with lipid synthesis in the mycobacterial cell wall. Ethambutol inhibits arabinogalactan synthesis, impairing cell wall formation. Both drugs are valuable in resistant TB cases, though stability and dose-dependent toxicity require careful monitoring.
Pyrazinamide and Para-Amino Salicylic Acid (PAS)
Pyrazinamide is effective in acidic environments such as macrophage phagosomes, making it crucial in shortening TB therapy duration. PAS, a structural analogue of para-aminobenzoic acid, inhibits folate metabolism. PAS undergoes chemical degradation through decarboxylation and hydrolysis, limiting its stability.
Anti-Tubercular Antibiotics
Rifampicin and Rifabutin
Rifampicin is a rifamycin antibiotic that inhibits DNA-dependent RNA polymerase, making it highly bactericidal. Rifabutin, a related compound, offers improved activity against resistant strains. Both drugs are prone to oxidative degradation and require protection from light and moisture.
Cycloserine, Streptomycin, and Capreomycin
Cycloserine interferes with cell wall synthesis by inhibiting alanine racemase. Streptomycin, an aminoglycoside antibiotic, was the first effective anti-TB drug and acts by inhibiting protein synthesis. Capreomycin sulphate is a cyclic peptide antibiotic used in multidrug-resistant TB. These antibiotics demonstrate how chemical structure influences ribosomal binding and antimicrobial potency.
Urinary Tract Anti-Infective Agents
Quinolones: Chemistry and SAR
Quinolones are synthetic antibacterial agents targeting DNA gyrase and topoisomerase IV. SAR studies reveal that substitutions at positions 1, 6, and 7 of the quinolone nucleus enhance antibacterial potency and spectrum. Fluorination, in particular, improves cell penetration and activity.
Important Quinolone Derivatives
Nalidixic acid represents the first-generation quinolone, mainly active against gram-negative urinary pathogens. Newer fluoroquinolones such as norfloxacin, enoxacin, ciprofloxacin, ofloxacin, lomefloxacin, sparfloxacin, gatifloxacin, and moxifloxacin exhibit broader spectrum, improved pharmacokinetics, and reduced resistance. Chemical degradation often involves photolysis and oxidation, requiring careful formulation.
Miscellaneous Urinary Tract Anti-Infectives
Furazolidone and Nitrofurantoin
Nitrofurantoin and furazolidone are nitrofuran derivatives that damage bacterial DNA through reactive intermediates. Nitrofurantoin is particularly effective for uncomplicated UTIs due to high urinary concentration. Chemical instability under alkaline conditions necessitates controlled storage.
Methenamine
Methenamine acts as a urinary antiseptic by releasing formaldehyde in acidic urine. Its activity depends on urinary pH, highlighting how chemical environment influences therapeutic efficacy.
Antiviral Agents: Targeting Viral Replication
Introduction to Antiviral Chemotherapy
Viruses rely on host cellular machinery, making selective drug design challenging. Antiviral agents inhibit specific viral enzymes or replication steps, limiting viral spread while preserving host cell function.
Anti-Influenza Agents
Amantadine and rimantadine hydrochloride inhibit viral uncoating by blocking ion channels. Resistance and limited spectrum have reduced their current use, but they represent early successes in antiviral drug design.
Anti-Herpes and Anti-DNA Virus Agents
Idoxuridine trifluoride was among the first antiviral nucleoside analogues. Acyclovir revolutionized herpes treatment by selectively inhibiting viral DNA polymerase. Ganciclovir expanded activity against cytomegalovirus but requires careful toxicity monitoring.
Anti-HIV Agents
Zidovudine, didanosine, zalcitabine, and lamivudine are nucleoside reverse transcriptase inhibitors that block viral DNA synthesis. Non-nucleoside inhibitors such as loviride and delavirdine bind directly to reverse transcriptase. Protease inhibitors including saquinavir, indinavir, and ritonavir prevent viral maturation, forming the backbone of combination antiretroviral therapy.
Broad-Spectrum Antivirals
Ribavirin exhibits activity against multiple RNA viruses by interfering with nucleic acid synthesis. Its chemical instability and toxicity profile require cautious clinical use.