Structural modification of natural products is necessary to improve their properties for clinical use. Modifications aim to increase potency and selectivity, improve pharmacokinetic properties, eliminate toxicity, simplify structures while retaining activity, and generate patentable compounds. Key points of modification include eliminating unnecessary structural elements, introducing functional groups to boost binding, simplifying large complex structures, reducing chiral centers, increasing activity or selectivity, and improving physico-chemical properties. Examples provided demonstrate how natural products like cocaine, physostigmine, lovastatin, vancomycin, retinoic acid, and artemisinin were modified to develop safer, more effective drugs.

1. Drugs developed based on chemical
modification

2. Introduction
• The secondary metabolites of living organisms do not exist for the healthcare of human beings. Although the
natural products are normally valuable , mostly they cant’t be directly used in clinical applications.
• Structural modifications are necessary and involve several aspects.
Why should we modify natural products??????
The strategy for structural modification is to:
• Increase potency and selectivity
• Improve physico-chemical, biochemical, and pharmacokinetic property
• Eliminate or reduce toxicity
• Simplify the structural complexity - removal of redundant atoms and chirality while retaining activities
• Generate patentable compounds.

3. General features of Natural compounds
Structural diversity and complexity
More sp3-hybridized (Single bonded) C atom,and less N atoms
Existence of Chiral centers & Stereochemistry
Many structures of natural compounds are not involved in binding to the target.
Unnecessary moieties need to be removed from lead compounds
Most natural compounds have more C,H, and O atoms, and less N atoms (Except Leguminosae).
N atoms-highly nucleophilc and versatile atom in many aspects
Introduction or modification of various nitrogen atoms is an important molecular operation in lead compound optimization.
Most natural compounds – contain chiral centers-leading to stereo cis/trans
Chiral centres not participating in binding-trimmed out

4. Key points in structural modification
• 1. eliminate structurally-unnecessary factors
• Ex: Cocaine Procaine, Tetracaine, Lidocaine
Cocaine: Alkaloid (coca species, Erythroxylum coca and Erythroxylum novogranatense)
• Local anaesthetic
• Ex: Physostigmine Pyridostigmine bromide, Neostigmine bromide
• From Physostigma venenosum
• parasympathomimetic alkaloid (a substance that stimulates the parasympathetic nervous system (PSNS)) (acetylcholine (ACh) is
the neurotransmitter used by the PSNS)
• It is Acetylcholinesterase inhibitor- prevents hydrolysis of acetylcholine-Hence enhance the effect of acetylcholine- improving
strength of muscle
• Improving muscle tone in patients with myasthenia gravis.
• Intense Vasoconstrictor
• Potential Cardiovascular toxicity
Safer, non-addictive
Chemical instability
Tertiary amine: Can cross BBB to reach CNS
causing CNS toxicity
Simple, non-chiral
Quartery ammonium salt:Poor penetration to CNS

6. Compounds with small size have structural space to add atoms,
groups, or moieties
Ex: introducing a hydrogen donor or acceptor may increase the affinity
to receptors
or adding solubilizing groups raises the solubility or modulates the
partition property to benefit or avoid crossing the blood brain barrier

8. Simplifying structures
Large size and complex structure : unfavorable for solubility, absorption and metabolism.
• Objective: To decrease the molecular size and to eliminate the unnecessary functional groups
Ex: From halichondrin B to eribulin
• Halochondrin B, a marine natural product, was originally isolated from a Japanese rare marine sponge
(Halichondria okadai)
• Eribulin, a novel synthetic antimicrotubule agent that binds to the vinca domain of tubulin and
inhibits the polymerization of tubulin, offers a new treatment option for metastatic breast cancer or
locally advanced breast cancer.
• Eribulin mesylate is a structurally simplified synthetic macrocyclic ketone analogue of halichondrin B,
an antimitotic agent that exhibits potent anticancer effects in both in vitro and in vivo models of
cancer
Eribulin

9. Diminishing chiral centers
• From lovastatin to “statin” drug
• Lovastatin: a cholesterol-lowering natural product
• Pleurotus ostreatus and the closely related Pleurotus spp.
• Lovastatin contains eight asymmetrical carbon atoms (red dots)
• The lactone ring opens in cells by enzymatic catalysis to form a (R,R)-β,δ-dihydroxypentanoic acid moiety, which
structurally mimics HMG and constitutes the pharmacophoric feature.
Two cabon atoms in the lactone ring is crucial for binding
Chirality of lower 6 carbons are not necessary for binding
Based on lovastatin structure, Statin drugs- atorvastatin and rosuvastatin were developed: No asymmetric factors

10. Increasing activity or selectivity
• From vancomycin to telavancin and dalbavancin
• Vancomycin-a natural antibiotic used to treat a number of bacterial infections. However, in resistant bacteria
vancomycin could not prevent cell wall synthesis.
• To overcome resistance to vancomycin, second generation drugs were developed.
• Telavancin-a semisynthetic multifunctional lipoglycopeptide, disrupts both cell wall synthesis and cell membrane
integrity in methicillin resistant Staphylococcus aureus.
Televancin Dalbavancin

11. Increasing metabolic stability
• From retinoic acid to tamibarotene
• All-trans-retinoic acid is a metabolite of vitamin A (retinol) that mediates and induces growth and differentiation of
epithelial cells.
• Clinically ATRA is indicated for the treatment of acute promyelocytic leukemia and acne. However, serious adverse effects
and its chemical instability restrict its application.
• Tamibarotene , is structurally quite different from that of ATRA, yet it resembles the pharmacophore of ATRA. It is more
active and stable .
• Tamibarotene was approved by the FDA in 2005 for the treatment of acute promyelocytic leukemia
Tamibarotene

12. Improving physico-chemical properties
From artemisinin to dihydroartemisinin, artemether, artesunate, and artether
• anti-malarial drugs against chloroquine-resistant Plasmodium falciparum
• Artemisinin is a sesquiterpene.
• reducing the lactone moiety of artemisinin with NaBH4 under low temperature == dihydroartemisinin – stronger
activities than artemisinin.
• The poor biopharmaceutic properties and low bioavailability of artemisinin restricts its clinical application.
• Dihydroartemesinin derivatives: dihydroartemisinin C10-monoesters of diacids –water soluble artemisinin related
drugs for injectable formulations.