Medicinal Chemistry of Antimalarial & Antituberculosis Drugs

Learning Outcomes

  • By the end of the lecture students should be able to:
    • Explain structural features that determine the pharmacology of antimalarial & antituberculosis drugs.
    • Explain structural features that govern the pharmacokinetics of these drugs.

ANTIMALARIAL DRUGS – GENERAL POINTS

  • Malaria is caused by 4 Plasmodium species.
  • Drug choice depends on species-specific efficacy.
  • Four medicinal-chemistry classes discussed:
    • Artemisinin derivatives.
    • Quinine and related cinchona alkaloids.
    • 4-Aminoquinolines.
    • 8-Aminoquinolines.

Artemisinin & Key Derivatives

  • Natural sesquiterpene lactone from Artemisia annua; used historically in Traditional Chinese Medicine.
  • Highly potent vs. P.  falciparumP.\;falciparum but native artemisinin suffers from:
    • Very poor aqueous solubility.
    • Very poor lipid solubility.
Lead Optimisation Pathway
  1. Reduction of the lactone ➜ dihydroartemisinin (DHA)
    • Improves physicochemical profile (↑ polarity, retains activity).
  2. Lipid-soluble ethers (alkylation of the new OH):
    • Artemether (O-methyl ether)
    • Arteether (O-ethyl ether)
    • Both available as i.m. injections; artemether also as oral combo with lumefantrine.
  3. Water-soluble esters (esterification of the OH):
    • Artesunate (hemisuccinate ester) ➜ powder for injection & oral tablets.
Structure–Activity Relationship (SAR)
  • Endoperoxide bridge (–O–O–) is absolutely essential:
    • Undergoes Fe(II)-mediated cleavage in the parasite, generating free radicals ➜ oxidative membrane damage.
    • Endoperoxide→Fe2+alkoxy/oxygen radicals→lipid peroxidation\text{Endoperoxide} \xrightarrow{Fe^{2+}} \text{alkoxy/oxygen radicals} \to \text{lipid peroxidation}
  • Lactone ring itself NOT required for activity, but its modification (reduction → ethers/esters) fine-tunes PK properties.
  • Any change that removes or reduces the endoperoxide abolishes antimalarial activity.

Quinine & Cinchona Alkaloids

  • Isolated from bark of Cinchona spp.; historically first effective antimalarial.
  • Fluorescent, bitter alkaloid.
Essential Structural Elements
  • Quinoline ring delivers DNA-intercalation / heme-binding pharmacophore.
    • 2-methoxy group is not essential for activity; removal lowers phototoxicity.
  • C4 secondary alcohol adjacent to the quinuclidine ring is crucial.
    • Oxidation or esterification of this OH ➜ marked loss of potency.
  • Quinuclidine tertiary amine at C9 is vital for activity.
  • Introduction of 2´-CF$3$ on the side-chain phenyl generated mefloquine (increased potency & t${1/2}$).
Chirality Matters
  • Natural quinine: 8R,9S8R,9S configuration = active antimalarial isomer.
  • Epimerisation ( 8S,9R8S,9R ) decreases activity.
  • Family overview (R$1$ = methoxy, R$2$ = side chain):
    • quinine, quinidine, dihydroquinine, dihydroquinidine, cinchonine, cinchonidine differ in C=C saturation & R$1$/R$2$.
Key Derivative: Mefloquine
  • Incorporates two CF$_3$ groups on the aryl ring.
  • Tetracyclic, highly lipophilic; long elimination half-life (useful for prophylaxis).

4-Aminoquinolines

  • Prototype: Chloroquine; others: hydroxychloroquine, amodiaquine.
Pharmacophoric Requirements
  1. 4-Aminoquinoline core.
  2. Dialkylaminoalkyl side chain attached at C4 via a p-aminobond.
    • Optimal length = 2–5 saturated carbons (chloroquine has 3).
    • Terminal tertiary amine indispensable; protonates to accumulate in acidic parasite food vacuole.
    • Unsaturation in chain tolerated.
  3. Modifications:
    • Addition of a β-OH group on one ethyl (hydroxychloroquine) lowers toxicity & ↑ plasma level.
    • Aromatic ring insertion in side chain (amodiaquine) reduces toxicity.
Representative Structures
  • Chloroquine: two Cl atoms on quinoline ring, N-diethyl side chain.
  • Hydroxychloroquine: identical but with β-OH on one ethyl.
  • Amodiaquine: side chain incorporates para-aminophenol motif.

8-Aminoquinolines

  • Prototype: Primaquine; newer: tafenoquine; older & more toxic: pamaquine.
Mechanistic Note
  • Drug undergoes auto-oxidation forming a radical anion at the 8-amino group ➜ redox cycling & oxidative damage to latent hepatic hypnozoites (radical cure of vivax/ovale).
SAR Highlights
  • Pentyl side chain at N8 = maximal activity; longer chains ↓ potency.
  • 6-Methoxy group contributes modestly; replacing OCH$3$ with OC$2$H$5$ ⇒ ↓ activity + ↑ toxicity; replacing with CH$3$ ⇒ inactive.
  • Introduction of halogens increases toxicity.
  • Pamaquine vs. Primaquine: ethyl substitution on side chain makes pamaquine less efficacious & more toxic.
  • Tafenoquine: bulky, lipophilic, long t$_{1/2}$, once-weekly prophylactic dosing.

ANTITUBERCULOSIS DRUGS – GENERAL

  • First-line agents covered:
    1. Isoniazid (INH).
    2. Rifamycins (rifampin, rifabutin).
    3. Ethambutol.

Isoniazid (INH)

  • Prodrug requiring activation by the mycobacterial catalase-peroxidase KatG.
Activation Cascade

INH→H<em>2O</em>2KatGisonicotinoyl radical→NAD+INH–NAD adduct\text{INH} \xrightarrow[H<em>2O</em>2]{KatG} \text{isonicotinoyl radical} \xrightarrow{NAD^+} \text{INH–NAD adduct}

  • INH–NAD adduct inhibits InhA (NADH-dependent enoyl-ACP reductase) ➜ blocks mycolic-acid synthesis ➜ defective cell wall.
SAR Observations
  • Isonicotinoyl (pyridine) ring directs binding to KatG & later to NAD$^+$.
    • Replacing the pyridine with other aromatics (e.g. piperidine, phenyl) abolishes antitubercular activity.
  • Hydrazide (–CONHNH$_2$) moiety: N1 (terminal) must be free for activation; N2 may tolerate limited substitution (e.g. isopropyl retains some activity but adds stimulant properties).
  • Radical anion pathways also proposed for alternative activation routes.

Rifamycins

  • Macrocyclic antibiotics produced by Streptomyces mediterranei; function as RNA-polymerase inhibitors.
Essential Structural Features
  1. C2 & C3 phenolic oxygens form H-bonds with β-subunit of bacterial RNA polymerase.
  2. C21 & C23 hydroxyls participate in chelating a Zn$^{2+}$ ion at the enzyme.
    • Acetylation of either C21 or C23 ⇒ inactive.
  3. Conjugated double bonds within ansa (macro) ring must remain; hydrogenation diminishes activity.
  4. Macrocyclic integrity crucial; ring opening → drastic loss of potency.
Clinically Relevant Members
  • Rifampin (rifampicin): first-line oral/i.v.; broad anti-TB.
  • Rifabutin: more lipophilic, longer t$_{1/2}$; preferred in rifampin-resistant or HIV co-infected TB.

Ethambutol

  • Symmetric ethylene diamine derivative.
Critical Functional Groups
  • Two primary alcohols (–CH$_2$OH) & two secondary amines essential.
    • Removal or modification (acetyl, sulfonyl, nitrosyl) of OH or NH groups abolishes activity.
  • Stereochemistry: only the (S,S) enantiomer is active; (R,R) inactive.
  • Carbon spacing between nitrogens:
    • Exactly two carbons (ethylene) optimum; further extension decreases potency.
  • Introduction of large alkyl chains reduces activity & may increase toxicity.

Integrative & Practical Notes

  • Many antimalarials rely on accumulation in acidic parasite vacuoles (chloroquine class) or free-radical generation (artemisinin; 8-aminoquinolines).
  • Tuberculosis drugs showcase prodrug activation (INH) & macrocycle-enzyme interactions (rifamycins).
  • SAR knowledge enables:
    • Prediction of cross-resistance (e.g. rifampin vs. rifabutin).
    • Design of derivatives with improved PK/PD (e.g. artemether vs. artemisinin).
  • Ethical/clinical consequences:
    • Overuse of chloroquine led to resistance, prompting artemisinin-based combination therapies (ACTs).
    • In TB, misuse of rifampin fosters MDR-TB; emphasizes need for directly-observed therapy.
  • Real-world relevance: understanding endoperoxide radical formation informs design of next-gen peroxide antimalarials; knowledge of KatG mutations guides molecular diagnostics for INH resistance.