Drug discovery from natural products: lead selection and optimization (artemisinin, andrographolide examples) MCQs With Answer

Drug discovery from natural products: lead selection and optimization (artemisinin, andrographolide examples) MCQs With Answer

This short MCQ set is designed for M.Pharm students studying phytochemistry and drug discovery. It focuses on principles of lead selection and optimization using real-world natural product examples — artemisinin (antimalarial) and andrographolide (anti-inflammatory/antiviral scaffold). Questions cover isolation, structure–activity relationships (SAR), semisynthetic derivatization, pharmacokinetics, ADME/Tox screening, formulation strategies and resistance issues. The goal is to deepen understanding of how natural leads are evaluated and chemically or formulation-wise optimized to improve potency, selectivity, solubility and safety — integrating medicinal chemistry, pharmacology and development considerations essential for postgraduate training.

Q1. Which structural feature of artemisinin is essential for its antimalarial activity?

• Peroxide (endoperoxide) bridge
• Gamma-lactone ring
• Large hydrophobic side chain
• Phenolic hydroxyl group

Correct Answer: Peroxide (endoperoxide) bridge

Q2. Which semisynthetic derivative of artemisinin is a water-soluble prodrug commonly used in severe malaria?

• Artemether
• Dihydroartemisinin
• Artesunate
• Arteether

Correct Answer: Artesunate

Q3. Dihydroartemisinin (DHA) is best described as:

• An inactive metabolite formed from artemisinin
• The primary active metabolite of many artemisinin derivatives
• A synthetic analogue with a nitrile group
• A peptide-conjugated artemisinin derivative

Correct Answer: The primary active metabolite of many artemisinin derivatives

Q4. A common resistance mechanism to artemisinin in Plasmodium involves mutations in:

• Hemoglobin gene
• Kelch13 protein
• Calmodulin
• P-glycoprotein efflux pump

Correct Answer: Kelch13 protein

Q5. Which lead optimization strategy was used to produce artemether from artemisinin?

• Introduction of a sugar moiety
• Reduction of the lactone ring
• Etherification to increase lipophilicity
• Halogenation to increase metabolic stability

Correct Answer: Etherification to increase lipophilicity

Q6. Key criteria in selecting a natural product as a drug lead include all EXCEPT:

• Demonstrated in vitro potency and selectivity
• High structural complexity preventing any modification
• Synthetic accessibility or semisynthetic potential
• Favourable preliminary ADME/Tox profile

Correct Answer: High structural complexity preventing any modification

Q7. Which property of andrographolide most limits its oral bioavailability?

• Excessive aqueous solubility
• Rapid hepatic metabolism and poor permeability
• Strong basicity causing gastric trapping
• High molecular weight (>800 Da)

Correct Answer: Rapid hepatic metabolism and poor permeability

Q8. Neoandrographolide differs from andrographolide primarily by having:

• An additional hydroxyl at C-3
• A glycosidic sugar moiety
• An aromatic ring fused to the core
• A halogen substituted on the lactone

Correct Answer: A glycosidic sugar moiety

Q9. Which experimental assay is most appropriate for early assessment of cytotoxicity during natural product lead optimization?

• In vivo efficacy in human volunteers
• MTT or resazurin cell viability assay on mammalian cell line
• Western blot for target protein expression
• Plasmodium growth inhibition assay

Correct Answer: MTT or resazurin cell viability assay on mammalian cell line

Q10. For artemisinin derivatives, why are combination therapies (ACTs) recommended?

• To reduce cost of treatment
• To increase the half-life of artemisinin itself
• To reduce emergence of resistance and improve cure rates
• To avoid the need for diagnostics

Correct Answer: To reduce emergence of resistance and improve cure rates

Q11. Which chemical modification is commonly used to improve water solubility of a lipophilic natural product lead?

• Conversion to a hemisuccinate ester (salt-forming prodrug)
• Introduction of additional aromatic rings
• Dehydration to form a double bond
• Attachment of long alkyl chains

Correct Answer: Conversion to a hemisuccinate ester (salt-forming prodrug)

Q12. Structure–activity relationship (SAR) studies for andrographolide typically focus on modifying:

• The endoperoxide bridge
• The lactone ring and hydroxyl substituents
• The peptide backbone
• The appended porphyrin group

Correct Answer: The lactone ring and hydroxyl substituents

Q13. Which ADME parameter would most directly predict oral absorption in lead optimization?

• Microsomal intrinsic clearance
• Caco-2 permeability
• hERG channel inhibition
• Plasma protein binding only

Correct Answer: Caco-2 permeability

Q14. A medicinal chemist wants to reduce first-pass metabolism of andrographolide. Which approach is rational?

• Increase polarity by adding multiple charged groups
• Design prodrugs or sterically block metabolically labile positions
• Remove the lactone entirely to make a smaller molecule
• Introduce multiple primary amines to increase clearance

Correct Answer: Design prodrugs or sterically block metabolically labile positions

Q15. Which formulation approach has been used to improve delivery and stability of artemisinin derivatives?

• Inhalable dry powder aerosols exclusively
• Nanoencapsulation and lipid-based formulations
• Formulation as a crystalline insoluble paste
• Complexation with cyclodextrin to permanently deactivate the drug

Correct Answer: Nanoencapsulation and lipid-based formulations

Q16. When optimizing a natural product lead, selectivity index is defined as:

• Ratio of IC50 against target pathogen to IC50 against host cells
• LogP value divided by molecular weight
• Percentage oral bioavailability at a fixed dose
• Number of chiral centers in the molecule

Correct Answer: Ratio of IC50 against target pathogen to IC50 against host cells

Q17. Which is a known advantage of semisynthesis from a natural product like artemisinin?

• It always makes the molecule completely non-toxic
• Allows chemical modification to improve drug-like properties while using the natural core
• Removes the need for pharmacokinetic studies
• Prevents any form of microbial resistance

Correct Answer: Allows chemical modification to improve drug-like properties while using the natural core

Q18. For andrographolide analogues, which modification is likely to enhance target binding without drastically increasing lipophilicity?

• Attachment of a small polar aromatic group to form additional hydrogen bonds
• Extending the molecule with long alkyl tails
• Replacing hydroxyls with larger bulky tert-butyl groups
• Introducing multiple halogens to all rings

Correct Answer: Attachment of a small polar aromatic group to form additional hydrogen bonds

Q19. In preclinical lead optimization, which toxicity assay is essential for predicting cardiotoxicity risk?

• CYP450 inhibition panel only
• hERG channel inhibition assay
• Bacterial Ames test exclusively
• Rodent skin irritation test only

Correct Answer: hERG channel inhibition assay

Q20. Which statement best summarizes why natural products remain important in modern drug discovery?

• They are always easier to synthesize than small synthetic molecules
• They provide diverse, biologically validated scaffolds that can be optimized for potency, selectivity and drug-like properties
• They never require ADME/Tox optimization
• They are universally non-patentable

Correct Answer: They provide diverse, biologically validated scaffolds that can be optimized for potency, selectivity and drug-like properties

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