Structure-Activity Relationship (SAR) in Drug Design

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Questions and Answers

What was the limitation of the first schistosomicides introduced, antimonials?

High cost for treatment

Convenient mode of administration

Toxicity (correct)

Short treatment courses

What is the essential group in Niridazole for its activity against all species of schistosome?

NH2

SO2

Nitro (correct)

Why is Niridazole not suitable for use as prophylaxis?

Low availability

CNS efficacy

CNS toxicity (correct)

High cost

Which of the following is true about Thioxanthones like lucanthone and hycanthone?

Associated with CNS toxicity Signup and view all the answers

What causes a loss of activity in Niridazole?

$H$ substitution Signup and view all the answers

What is the significance of introducing two amidine groups for high activity in trypanocides?

It increases the activity Signup and view all the answers

Which structural modification leads to compounds of reduced activity in trypanocides?

Replacement of benzene ring by other nuclei Signup and view all the answers

What distinguishes nitrofurans like Nifurtimox in terms of their properties?

They possess significant antiprotozoal activity along with antibacterial properties Signup and view all the answers

What action do organic arsenicals exhibit on trypanosomes?

Their action is parallel to their antisyphilic action Signup and view all the answers

What makes Melarsoprol effective against meningoencephalitic associated with late stages of T. gambiense and T. rhodesiense?

Its ability to penetrate the CNS Signup and view all the answers

What is the drug of choice for acute Chagas disease caused by T. cruzi?

Nifurtimox Signup and view all the answers

What is the major setback in the application of melarsoprol as a trypanocidal agent?

Reactive encephalopathy Signup and view all the answers

Which antidote is used to counteract the toxic effects of arsenic in cases of poisoning?

Dimercaprol Signup and view all the answers

Which parasitic worm disease is also known as Bilharziasis?

Schistosomiasis Signup and view all the answers

What are the three major species of schistosomes that infect humans?

Schistosoma japonicum, Schistosoma mansoni, Schistosoma haematobium Signup and view all the answers

What is an ideal quality expected from an anti-schistosomal agent?

Absence of side effects and toxicity in humans Signup and view all the answers

Which class of anti-schistosomal agents includes antimonials?

Organic Arsenicals Signup and view all the answers

Study Notes

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

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Description

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.