Structure-Activity Relationship (SAR) in Drug Design

Structure-Activity Relationship (SAR)

• The dimethyl derivative of stilbamidine is twice as active as stilbamidine itself
• Introduction of –NH, –CH3CO–NH, or alkoxy groups leads to a decrease in activity
• Two amidine groups are essential for high activity and must be attached directly to the aromatic nuclei

Trypanocidal Agents

• Introduction of a heterocyclic ring between two aromatic benzene nuclei gives a powerful trypanocidal activity
• Replacement of the benzene ring with other nuclei results in compounds with reduced activity
• Diamidinophenanthrene, formed through ring closure, exhibits only small trypanocidal activity

Nitrofurans

• Derivatives of 5-nitro-2-furaldehyde possess antiprotozoal activity in addition to antibacterial properties
• Nifurtimox is the drug of choice for acute Chagas disease caused by T. cruzi

Organic Arsenicals

• Melarsoprol (Arsobal) is a trivalent arsenical compound with antisyphilic and trypanocidal properties
• It penetrates the CNS and is effective against meningoencephalitic associated with the late stages of T. gambiense and T. rhodesiense infection
• Adverse reactions include potentially fatal reactive encephalopathy, and the antidote is dimercaprol

Antischistosomal Agents

• Schistosomiasis, also known as Bilharziasis, is a severe, debilitating, parasitic worm disease affecting about 200 million people worldwide
• The three major species infecting humans are Schistosoma haematobium, Schistosoma mansoni, and Schistosoma japonicum

Life Cycle and Host-Vector Control

• Cercariae penetrate the skin of humans, causing infection
• Symptoms include blood in urine, liver and spleen enlargement, and diarrhea
• Host-vector control involves the use of molluscicides against snails and provision of clean water supply

Chemotherapy

• An ideal anti-schistosomal agent should have absence of side effects and toxicity in humans, high activity against the three major species of schistosomes, and be effective after single or one-day treatment
• Classes of anti-schistosomal agents include antimonials, thioxanthones, nitrothiazoles, oxamniquine, and praziquantel

Antimonials and Thioxanthones

• Antimonials were the first schistosomicides introduced, but were severely limited by their toxicity and inconvenient mode of administration
• Thioxanthones, such as lucanthone and hycanthone, are examples of anti-schistosomal agents

Niridazole

• Niridazole was discovered by Lambert and co-workers in 1964 and is active against all species of schistosomes
• The nitro group is essential for its activity, and replacement with Cl, SO2, NH2, or H causes a loss of activity
• Niridazole is metabolized too quickly in low doses to be used as prophylaxis and is limited by CNS toxicity and lack of efficacy against S. japonicum

Learn about the relationships between chemical structure and biological activity in drug design. Explore how specific modifications impact the effectiveness of compounds through examples and guidelines.