Infectious diseases caused by fungi, protozoa, and helminths remain a significant burden, particularly in immunocompromised individuals and tropical regions. Alongside these pathogens, bacterial infections once dominated by sulphonamides continue to shape antimicrobial history. Unit 4 explores antifungal agents, antiprotozoal and anthelmintic drugs, and the chemistry and structure–activity relationships (SAR) of sulphonamides, sulfones, and folate reductase inhibitors. This article presents a clear, news-style overview of their chemical basis and therapeutic relevance.
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Antifungal Agents: Targeting Unique Fungal Structures
Antifungal Antibiotics
Antifungal antibiotics are primarily derived from microbial sources and act on fungal cell membranes or mitotic processes. Amphotericin B, nystatin, and natamycin belong to the polyene class and exert their action by binding to ergosterol in fungal cell membranes. This interaction creates pores that increase membrane permeability, leading to cell death. Amphotericin B is particularly effective in systemic fungal infections, though its use is limited by nephrotoxicity.
Griseofulvin, another antifungal antibiotic, acts differently by disrupting mitotic spindle formation. It accumulates in keratinized tissues, making it valuable in treating dermatophytic infections of skin, hair, and nails.
Synthetic Antifungal Agents
Synthetic antifungal drugs mainly interfere with ergosterol synthesis. Imidazole derivatives such as clotrimazole, econazole, miconazole, oxiconazole, butoconazole, and tioconazole inhibit fungal cytochrome P450 enzymes, blocking ergosterol production.
Ketoconazole marked a milestone as the first orally active azole, though hepatic toxicity limited its use. Later triazoles—including fluconazole, itraconazole, and terconazole—offered improved selectivity, safety, and broader antifungal spectrum.
Naftifine hydrochloride and tolnaftate are allylamine derivatives effective in superficial mycoses, acting earlier in sterol biosynthesis. SAR studies show that lipophilicity and heterocyclic substitutions enhance antifungal potency and tissue penetration.
Anti-Protozoal Agents: Controlling Parasitic Infections
Nitroimidazole Derivatives
Metronidazole, tinidazole, and ornidazole are cornerstone drugs against amoebiasis, giardiasis, and trichomoniasis. These agents generate reactive nitro radicals under anaerobic conditions, damaging protozoal DNA. Their chemical stability and high selectivity make them first-line therapy for anaerobic protozoal infections.
Other Anti-Protozoal Drugs
Diloxanide and iodoquinol are luminal amoebicides used to eradicate intestinal cysts. Pentamidine isethionate is effective against African trypanosomiasis, while eflornithine inhibits polyamine synthesis in protozoa.
Atovaquone disrupts mitochondrial electron transport and is used in protozoal infections such as toxoplasmosis and pneumocystis pneumonia. Chemical modifications in these agents improve selectivity and reduce host toxicity.
Anthelmintic Agents: Eliminating Parasitic Worms
Anthelmintic drugs target helminths by disrupting neuromuscular activity or metabolic pathways. Diethylcarbamazine citrate is effective against filarial infections by altering parasite membrane function.
Benzimidazoles such as thiabendazole, mebendazole, and albendazole inhibit microtubule synthesis, impairing glucose uptake in worms. SAR studies reveal that carbamate substitutions enhance anthelmintic activity.
Niclosamide interferes with oxidative phosphorylation in cestodes, while praziquantel increases membrane permeability to calcium, causing paralysis of schistosomes.
Ivermectin, a macrocyclic lactone, enhances inhibitory neurotransmission in parasites, making it one of the most effective broad-spectrum anthelmintics in modern therapy.
Sulphonamides and Sulfones: Pioneers of Antibacterial Chemotherapy
Historical Development and Chemistry
Sulphonamides were the first successful systemic antibacterial agents, marking the beginning of chemotherapeutic control of infections. Chemically, they are structural analogues of para-aminobenzoic acid (PABA), allowing them to inhibit bacterial folic acid synthesis.
Classification and SAR of Sulphonamides
SAR studies show that a free para-amino group and a sulphonamide linkage are essential for activity. Substitutions on the heterocyclic ring influence solubility, duration of action, and antibacterial spectrum.
Important sulphonamides include sulphamethizole, sulfisoxazole, sulphamethizine, sulfacetamide, sulphapyridine, sulfamethoxazole, and sulphadiazine.
Specialized derivatives such as mefenide acetate are used topically, while sulfasalazine finds application in inflammatory bowel disease due to its dual antimicrobial and anti-inflammatory action.
Folate Reductase Inhibitors: Enhancing Antibacterial Efficacy
Trimethoprim and Cotrimoxazole
Trimethoprim selectively inhibits bacterial dihydrofolate reductase, blocking DNA synthesis. When combined with sulfamethoxazole as cotrimoxazole, it produces a synergistic effect by sequential blockade of folate metabolism. This combination is widely used in urinary tract infections and opportunistic infections.
Sulfones: A Special Class of Antimicrobial Agents
Dapsone
Dapsone is a sulfone structurally related to sulphonamides. It inhibits folate synthesis and is primarily used in leprosy and certain dermatological conditions. Its long half-life and anti-inflammatory properties make it valuable in chronic therapy, though careful monitoring is required due to hematological toxicity.