Biguanides and dihydrotriazines – Cycloguanil and Proguanil MCQs With Answer

Biguanides and dihydrotriazines — Cycloguanil and Proguanil MCQs With Answer

Biguanides and dihydrotriazines, exemplified by proguanil and its active metabolite cycloguanil, are key antimalarial agents covered in B. Pharm courses. This introduction summarizes chemical class, mechanism of action (DHFR inhibition), bioactivation of proguanil to cycloguanil via CYP2C19, pharmacokinetics, resistance due to plasmodial DHFR mutations, clinical uses including prophylaxis and combination therapy with atovaquone, adverse effects and relevant drug interactions. Emphasis is placed on structure–activity relationships, therapeutic rationale and implications for dispensing. Keywords: Biguanides, dihydrotriazines, cycloguanil, proguanil, antimalarial, DHFR inhibition, CYP2C19, resistance, pharmacokinetics. Laboratory monitoring and awareness of CYP polymorphisms are clinically relevant for dosing and predicting efficacy. Now let’s test your knowledge with 30 MCQs on this topic.

Q1. Which chemical class does proguanil belong to?

• Biguanides
• Dihydrotriazines
• Sulfonamides
• Quinolines

Correct Answer: Biguanides

Q2. Cycloguanil is best described as:

• A CYP2C19 inhibitor
• An active dihydrotriazine metabolite of proguanil
• A tetracycline antibiotic
• An atovaquone analog

Correct Answer: An active dihydrotriazine metabolite of proguanil

Q3. The primary molecular target of cycloguanil in Plasmodium is:

• Plasmodial dihydrofolate reductase (DHFR)
• Plasmodial cytochrome b
• 70S ribosomal subunit
• ATP synthase

Correct Answer: Plasmodial dihydrofolate reductase (DHFR)

Q4. Proguanil is converted to cycloguanil predominantly by which enzyme?

• CYP3A4
• CYP1A2
• CYP2C19
• CYP2D6

Correct Answer: CYP2C19

Q5. Resistance to cycloguanil is most commonly associated with:

• Mutations in the plasmodial DHFR gene
• Overexpression of cytochrome P450 enzymes
• Efflux pump upregulation in hepatocytes
• Increased renal clearance

Correct Answer: Mutations in the plasmodial DHFR gene

Q6. Which clinical formulation pairs proguanil with atovaquone for malaria prophylaxis and treatment?

• Malarone
• Fansidar
• Coartem
• Sulfadoxine

Correct Answer: Malarone

Q7. The mechanism by which proguanil enhances atovaquone activity (in combination) is primarily due to:

• Proguanil’s direct DHFR inhibition only
• Proguanil’s mitochondrial membrane potential disruption aiding atovaquone
• Induction of drug-metabolizing enzymes
• Chelation of atovaquone increasing its solubility

Correct Answer: Proguanil’s mitochondrial membrane potential disruption aiding atovaquone

Q8. Which statement about proguanil’s pharmacological profile is correct?

• Proguanil is active only as the parent compound and not metabolized
• Proguanil acts solely as a competitive inhibitor of DHPS
• Proguanil is a prodrug that is bioactivated to cycloguanil
• Proguanil is administered parenterally due to poor oral absorption

Correct Answer: Proguanil is a prodrug that is bioactivated to cycloguanil

Q9. A patient who is a CYP2C19 poor metabolizer will most likely have:

• Increased conversion of proguanil to cycloguanil
• Decreased formation of cycloguanil from proguanil
• Enhanced renal elimination of proguanil
• More rapid onset of cycloguanil action

Correct Answer: Decreased formation of cycloguanil from proguanil

Q10. The principal clinical use of proguanil/cycloguanil derivatives is:

• Treatment of bacterial sepsis
• Antifungal therapy
• Antimalarial prophylaxis and treatment
• Antiviral prophylaxis

Correct Answer: Antimalarial prophylaxis and treatment

Q11. Adverse effects commonly associated with proguanil include:

• Severe nephrotoxicity as the most frequent reaction
• Gastrointestinal disturbances and headache
• Immediate anaphylaxis in most patients
• Marked hyperglycemia

Correct Answer: Gastrointestinal disturbances and headache

Q12. Which mutation is classically linked to high-level resistance to cycloguanil in Plasmodium falciparum?

• S108N in DHFR
• K76T in pfcrt
• N86Y in pfmdr1
• G449C in CYP2C19

Correct Answer: S108N in DHFR

Q13. The term “dihydrotriazine” refers to which structural feature present in cycloguanil?

• A six-membered aromatic ring with sulfur
• A saturated triazine ring system (dihydrotriazine)
• A beta-lactam ring
• An imidazole heterocycle

Correct Answer: A saturated triazine ring system (dihydrotriazine)

Q14. Which pharmacokinetic property is vital when considering proguanil dosing for prophylaxis?

• Its extensive protein binding prevents tissue distribution
• Hepatic metabolism to cycloguanil affecting active exposure
• Primary elimination by enterohepatic recycling only
• Complete inactivation by gastric acid

Correct Answer: Hepatic metabolism to cycloguanil affecting active exposure

Q15. Which drug interaction would most likely decrease cycloguanil formation from proguanil?

• Co-administration with a strong CYP2C19 inhibitor
• Co-administration with a CYP2C19 inducer
• Co-administration with a proton pump inhibitor that does not affect CYP2C19
• Co-administration with oral calcium supplements

Correct Answer: Co-administration with a strong CYP2C19 inhibitor

Q16. Structure–activity relationship: which moiety in proguanil is essential for conversion to cycloguanil?

• Biguanide side chain
• Phenyl sulfonamide group
• Lactone ring
• Quinoline nucleus

Correct Answer: Biguanide side chain

Q17. Which laboratory monitoring may be relevant during prolonged high-dose therapy with DHFR inhibitors like cycloguanil?

• Complete blood count to monitor for myelosuppression
• Serum amylase for pancreatitis only
• Fasting glucose for hypoglycemia
• Urine ketones for ketoacidosis

Correct Answer: Complete blood count to monitor for myelosuppression

Q18. Which statement about proguanil’s intrinsic activity is true?

• Proguanil has no antimalarial effects until converted
• Proguanil possesses some intrinsic antimalarial activity independent of cycloguanil
• Proguanil is toxic to human mitochondria at therapeutic doses
• Proguanil acts as a sulfonamide analog at folate synthesis enzymes

Correct Answer: Proguanil possesses some intrinsic antimalarial activity independent of cycloguanil

Q19. Combining proguanil with a drug that selects for DHFR mutations is likely to:

• Reduce the risk of resistance development
• Increase selection pressure for DHFR-resistant parasites
• Enhance conversion to cycloguanil
• Eliminate need for combination therapy

Correct Answer: Increase selection pressure for DHFR-resistant parasites

Q20. Which pharmacological strategy is used to minimize resistance when using proguanil/cycloguanil?

• Monotherapy at high doses only
• Use in combination with drugs having different targets (e.g., atovaquone)
• Reduce dosing frequency to once monthly
• Use solely in pregnant women

Correct Answer: Use in combination with drugs having different targets (e.g., atovaquone)

Q21. During medicinal chemistry optimization, conversion of a biguanide to a dihydrotriazine generally impacts which property most directly?

• Affinity for bacterial ribosomes
• Binding to plasmodial DHFR and specificity
• Rate of renal excretion unchanged
• Conversion to an antiviral agent

Correct Answer: Binding to plasmodial DHFR and specificity

Q22. A pharmacist counseling a traveler should advise that atovaquone–proguanil should be started:

• One day before travel to the malarious area
• One month before travel
• At the time of first mosquito bite
• Not needed for short trips under 24 hours

Correct Answer: One day before travel to the malarious area

Q23. Which adverse effect is of special concern in prolonged treatment with antifolates such as cycloguanil?

• Folate deficiency–related hematological effects
• Severe hypokalemia
• Excessive hair growth
• Ototoxicity

Correct Answer: Folate deficiency–related hematological effects

Q24. Which property explains why proguanil is suitable for oral prophylaxis?

• Poor oral absorption and rapid degradation
• Good oral bioavailability and acceptable half-life for daily dosing
• Extensive first-pass elimination preventing systemic exposure
• Requirement for intravenous infusion only

Correct Answer: Good oral bioavailability and acceptable half-life for daily dosing

Q25. Which is a medicinal chemistry rationale for combining proguanil with atovaquone?

• Both target the same enzyme to double inhibition
• Different targets reduce the probability of cross-resistance
• They both inhibit human DHFR to boost efficacy
• They form an inactive complex in plasma

Correct Answer: Different targets reduce the probability of cross-resistance

Q26. In populations with a high prevalence of CYP2C19 poor metabolizers, one might expect:

• Increased cycloguanil levels in all patients
• Reduced cycloguanil formation leading to altered efficacy profiles
• Complete resistance to atovaquone only
• No clinical consequence for proguanil therapy

Correct Answer: Reduced cycloguanil formation leading to altered efficacy profiles

Q27. Which laboratory method is most appropriate to detect DHFR gene mutations linked to cycloguanil resistance?

• Genotypic PCR-based assays
• Serum enzyme-linked immunosorbent assay for DHFR protein
• Complete blood count
• Urinalysis for drug metabolites

Correct Answer: Genotypic PCR-based assays

Q28. Which of the following is TRUE regarding cycloguanil’s selectivity?

• Cycloguanil inhibits human DHFR more potently than plasmodial DHFR
• Cycloguanil preferentially inhibits plasmodial DHFR over human DHFR
• Cycloguanil acts primarily on bacterial DHFR
• Cycloguanil has no enzyme target and acts as an antiseptic

Correct Answer: Cycloguanil preferentially inhibits plasmodial DHFR over human DHFR

Q29. Which counseling point is important when dispensing atovaquone–proguanil tablets?

• Take with a fatty meal to enhance atovaquone absorption
• Take on an empty stomach to improve proguanil absorption only
• Avoid all fluids for two hours after dosing
• Do not use for prophylaxis—only treatment

Correct Answer: Take with a fatty meal to enhance atovaquone absorption

Q30. Which research focus would most likely improve the clinical utility of proguanil/cycloguanil derivatives?

• Developing agents that further increase DHFR mutation rates
• Designing molecules with improved activity against resistant DHFR variants
• Reducing oral bioavailability to limit systemic exposure
• Eliminating metabolism to inactive polar metabolites only

Correct Answer: Designing molecules with improved activity against resistant DHFR variants

G S Sachin

I am a Registered Pharmacist under the Pharmacy Act, 1948, and the founder of PharmacyFreak.com. I hold a Bachelor of Pharmacy degree from Rungta College of Pharmaceutical Science and Research. With a strong academic foundation and practical knowledge, I am committed to providing accurate, easy-to-understand content to support pharmacy students and professionals. My aim is to make complex pharmaceutical concepts accessible and useful for real-world application.

Mail- Sachin@pharmacyfreak.com