1. Drug simplification involves removing unnecessary structural groups from complex lead compounds to improve synthetic accessibility, pharmacokinetic profiles, and reduce side effects. 2. The steps of drug simplification include analyzing molecular complexity, determining important substructures, elucidating structure-activity relationships, and removing unnecessary motifs. 3. Simplification of morphine involves sequentially removing rings, from E to BCDER. This demonstrates that certain rings like the oxygen bridge are not essential for analgesic activity. Simplified analogues like benzomorphans and pethidine retain analgesic properties.

1. An assignment on
Drug simplification
Submitted to:-
Abdul Motaleb Bhuiyan
Associate professor & Chairman
University of science and technology,
Chittagong
Submitted by:-
Roll – 14301
Reg – 1078
Course Name: Medicinal Chemistry-I
Course No:-PHR-302
Department of Pharmacy
University of science and technology, Chittagong

2. A
Drug Simplification : Simplification is the way to produce new drug analogue from
large or complex lead compounds by truncating unnecessary groups which can not only
improve their synthetic accessibility but also improve their pharmacokinetic profiles
,reduce side effects and so on.
Fig:-Drug Simplification
Objective of drug simplification:
To synthesize the compound easily.
To prepare more effective and safe compound.
The compounds have positive effects on the pharmacokinetic or
pharmacodynamics profile.
Reducing the molecular weight and molecular complexity.
To generate simplified analogues.
Drug Simplification

3. For drug simplification the following steps should be followed.
1. Analyzing the molecular complexicity of target molecules.
 Identification of the number of rings on the complex lead compounds.
 Finding how the rings are connected ( linked ,fused or bridged).
 Finding the number and configuration of chiral centres.
2. Determination of the substructures or groups important for the biological activity.
3. The elucidation of the Structure Activity Relationship (SAR) and pharmacophores.
4. The removal of unnecessary structural motifs.
Steps of Drug Simplification :

4. Structural simplification of natural products (Morphine):-
Morphine is the prototype chemical structure of a large chemical class of psychoactive
drugs, consisting of opiate analgesics, cough suppressants, and dissociative
hallucinogens, among others.
ℳ opioid receptor 3D structure of Morphine Morphine
Bound to a morphine
antagonist
Simplification of Morphine undergoes the followings:-
1. Removal of ring “E”
2. Removal of ring “D”
3. Removal of ring “C” and “D”
4. Removal of “ B” “C” and “D” ring
5. Removal of “B”, “C”, “D” and “E” ring

5. Changes in properties of drug after simplification
 Butophanol is five to nine times as potent as morphine. A dose of approximately
0.03mg/kg butophanol decreased respiration similar to 10mg of morphine.
 Pentazocaine weakly antagonizes the analgesic effects of morphine and it is six
times less potent than morphine.
 Pathedine is ( 1/10)th as potent as morphine but efficiency is similar and it has
better oral absorption
 Methadone has less withdrawal symptom and that’s why it is used in
rehabilitation centre.
Removing the oxygen bridge gives a seriesof compounds called Morphinans.
Morphinans have useful analgesic activity.This demonastrate that the oxygen bridge is
not essential. (Kar, 2005)
Removal of ring “D”

6. 1.N-methyl morphinan:-
Fig:- N-methyl morphinan
2.N-phenyl ethyl morphinan
Fig:- N-phenyl ethyl morphinan
Opening of both C & D ring gives an interesting & useful group of compound called
Benzomorphans which are found to retain analgesic activity. (Kar, 2005)
20% more active than
morphine
15 times more active than
morphine
Removal of ring “D”& “C”

7. Features of Benzomorphans:-
 C & D are not essential for analgesics activity.
 Analgesic and Addiction are not necessarily co-exist.
 Benzomorphans are clinically useful compound with reasonable analgesic
activity.
 Benzomorphans bind to opoid receptora in the same manner as morphine and
morphinans. (Kar, 2005)
Removing rings B,C&D gives a series of compound known as 4-phenylpiperidines.
(Kar, 2005)
1.Pethidine:-
Benzomorphan
Pentazocine:-
1.Long term effect
2.Very low risk of addition
Removal of ring “D”& “C”& “B”

8. Fig:- Pethidine
It is an weaker analgesic than morphine.It has a rapid onset and shorter duration of
action.As a result,it has been used as an analgesic in childbirth.
2.Fentanyl:-
Features:-
 These drugs lack a phenolic group and very lipophilic,as a result they can cross
the BBB more efficiently.
 Fentanyl itself is up to 100 times more active than morphine as a sedative and
analgesic.

9. The analgesic methadone was discovered in Germany during the second world war and
has proved to be a useful agent. (Kar, 2005)
Fig:- Methadone
Uses:- used over the drug addict persons due to its having less withdrawal symptoms.
References:-
1.Kar, Ashutosh. 2005. Medicinal Chemistry. New Delhi : New Age International
Publishers, 2005. pp. 241-271.
2.Kumar, Dr Sumit. 2016. Structure Activity Relationship of OPIOD. SlideShare.
[Online] september 28, 2016. https://www.slideshare.net/sumit2apr/structure-
activity-relationship-main.
3.Tripathi, KD. 2019. Essentials of Medical Pharmacology. 8th. New Delhi : JAYPEE
BROTHERS MEDICAL PUBLISHERS, 2019. p. 497.
Removal of ring “D” “C” “B” & “E”