Details of the Drug

General Information of Drug (ID: DMBL79I)

• Drug Name: Proguanil
• Synonyms: Bigumal; Chlorguanid; Chlorguanide; Chloriguane; Chloroguanide; Paludrin; Proguanile; Proguanilum; Proguanile [DCIT]; Diguanyl (hydrochloride); Drinupal (hydrochloride); Paludrine (TN); Paludrine (hydrochloride); Palusil (hydrochloride); Proguanil [INN:BAN]; Proguanilum [INN-Latin]; RP-3359; Tirian (hydrochloride); M-4888 (hydrochloride); SN-12837 (hydrochloride); N1-p-Chlorophenyl-N5-isopropylbiguanide; N-(4-Chlorophenyl)-N'-(1-methylethyl)imidodicarbonimidic diamide; N-(4-Chlorophenyl)-N'-(isopropyl)-imidodicarbonimidic diamide; N-(4-chlorophenyl)-N'-(propan-2-yl)imidodicarbonimidic diamide; (1E)-1-[amino-(4-chloroanilino)methylidene]-2-propan-2-ylguanidine; 1-(p-Chlorophenyl)-5-isopropylbiguanide; 1-Isopropyl-5-(4-chlorophenyl)biguanide

Indication

Disease Entry	ICD 11	Status	REF
Malaria	1F40-1F45	Approved	[1]

• Therapeutic Class: Antimalarials
• Drug Type: Small molecular drug
• #Ro5 Violations (Lipinski): 0:
  Molecular Weight (mw); 253.73
  Logarithm of the Partition Coefficient (xlogp); 1.5
  Rotatable Bond Count (rotbonds); 4
  Hydrogen Bond Donor Count (hbonddonor); 3
  Hydrogen Bond Acceptor Count (hbondacc); 1
• ADMET Property:
  BDDCS Class: Biopharmaceutics Drug Disposition Classification System (BDDCS) Class 1: high solubility and high permeability [2]
  Bioavailability: 60% of drug becomes completely available to its intended biological destination(s) [3]
  Half-life: The concentration or amount of drug in body reduced by one-half in 20 hours [4]
  Metabolism: The drug is metabolized via the liver []
  Water Solubility: The ability of drug to dissolve in water is measured as 9.09 mg/mL [2]
• Chemical Identifiers:
  Formula: C11H16ClN5
  IUPAC Name: (1E)-1-[amino-(4-chloroanilino)methylidene]-2-propan-2-ylguanidine
  Canonical SMILES: CC(C)N=C(N)/N=C(\\N)/NC1=CC=C(C=C1)Cl
  InChI: InChI=1S/C11H16ClN5/c1-7(2)15-10(13)17-11(14)16-9-5-3-8(12)4-6-9/h3-7H,1-2H3,(H5,13,14,15,16,17)
  InChIKey: SSOLNOMRVKKSON-UHFFFAOYSA-N
• Cross-matching ID:
  PubChem CID: 6178111
  ChEBI ID: CHEBI:8455
  CAS Number: 500-92-5
  DrugBank ID: DB01131
  TTD ID: D0P8RS
  INTEDE ID: DR1347

Molecular Interaction Atlas of This Drug

Drug Therapeutic Target (DTT)

DTT Name	DTT ID	UniProt ID	MOA	REF
Polypeptide deformylase (PDF)	TT9SL3Q	DEFM_HUMAN	Inhibitor	[5]

Drug-Metabolizing Enzyme (DME)

DME Name	DME ID	UniProt ID	MOA	REF
Cytochrome P450 3A4 (CYP3A4)	DE4LYSA	CP3A4_HUMAN	Substrate	[6]
Cytochrome P450 2E1 (CYP2E1)	DEVDYN7	CP2E1_HUMAN	Substrate	[7]
Cytochrome P450 2C9 (CYP2C9)	DE5IED8	CP2C9_HUMAN	Substrate	[8]
Mephenytoin 4-hydroxylase (CYP2C19)	DEGTFWK	CP2CJ_HUMAN	Substrate	[9]
Cytochrome P450 1A2 (CYP1A2)	DEJGDUW	CP1A2_HUMAN	Substrate	[7]

Drug Off-Target (DOT)

DOT Name	DOT ID	UniProt ID	Interaction	REF
Cytochrome P450 2D6 (CYP2D6)	OTZJC802	CP2D6_HUMAN	Gene/Protein Processing	[10]
Cytochrome P450 3A4 (CYP3A4)	OTQGYY83	CP3A4_HUMAN	Gene/Protein Processing	[10]

Molecular Expression Atlas of This Drug

• The Studied Disease: Malaria
• ICD Disease Classification: 1F40-1F45

Molecule Name	Molecule Type	Gene Name	p-value	Fold-Change	Z-score
Polypeptide deformylase (PDF)	DTT	PDF	8.87E-16	-0.54	-0.86
Cytochrome P450 2E1 (CYP2E1)	DME	CYP2E1	1.94E-06	7.00E-02	4.44E-01
Cytochrome P450 1A2 (CYP1A2)	DME	CYP1A2	7.09E-03	2.84E-02	1.20E-01
Mephenytoin 4-hydroxylase (CYP2C19)	DME	CYP2C19	6.34E-01	4.42E-03	2.22E-02
Cytochrome P450 2C9 (CYP2C9)	DME	CYP2C9	5.63E-01	-9.82E-03	-4.80E-02
Cytochrome P450 3A4 (CYP3A4)	DME	CYP3A4	7.29E-03	-3.47E-02	-1.80E-01

Drug-Drug Interaction (DDI) Information of This Drug

Coadministration of a Drug Treating the Disease Different from Proguanil (Comorbidity)

DDI Drug Name	DDI Drug ID	Severity	Mechanism	Comorbidity	REF
Sodium bicarbonate	DMMU6BJ	Moderate	Decreased absorption of Proguanil due to adsorption of Sodium bicarbonate.	Acidosis [5C73]	[11]
Arn-509	DMT81LZ	Moderate	Increased metabolism of Proguanil caused by Arn-509 mediated induction of CYP450 enzyme.	Acute myeloid leukaemia [2A60]	[11]
Cenobamate	DM8KLU9	Moderate	Decreased metabolism of Proguanil caused by Cenobamate mediated inhibition of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[12]
Brivaracetam	DMSEPK8	Minor	Decreased metabolism of Proguanil caused by Brivaracetam mediated inhibition of CYP450 enzyme.	Epilepsy/seizure [8A61-8A6Z]	[11]
Fedratinib	DM4ZBK6	Moderate	Decreased metabolism of Proguanil caused by Fedratinib mediated inhibition of CYP450 enzyme.	Myeloproliferative neoplasm [2A20]	[11]
Enzalutamide	DMGL19D	Moderate	Increased metabolism of Proguanil caused by Enzalutamide mediated induction of CYP450 enzyme.	Prostate cancer [2C82]	[13]
Armodafinil	DMGB035	Moderate	Decreased metabolism of Proguanil caused by Armodafinil mediated inhibition of CYP450 enzyme.	Solid tumour/cancer [2A00-2F9Z]	[14]

References

• [1] Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov. 2005 Sep;4(9):727-40.
• [2] BDDCS applied to over 900 drugs
• [3] Critical Evaluation of Human Oral Bioavailability for Pharmaceutical Drugs by Using Various Cheminformatics Approaches
• [4] Trend Analysis of a Database of Intravenous Pharmacokinetic Parameters in Humans for 1352 Drug Compounds
• [5] Transformation with human dihydrofolate reductase renders malaria parasites insensitive to WR99210 but does not affect the intrinsic activity of proguanil. Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):10931-6.
• [6] In vitro proguanil activation to cycloguanil is mediated by CYP2C19 and CYP3A4 in adult Chinese liver microsomes. Acta Pharmacol Sin. 2000 Aug;21(8):747-52.
• [7] Comparison of (S)-mephenytoin and proguanil oxidation in vitro: contribution of several CYP isoforms. Br J Clin Pharmacol. 1999 Aug;48(2):158-67.
• [8] Summary of information on human CYP enzymes: human P450 metabolism data. Drug Metab Rev. 2002 Feb-May;34(1-2):83-448.
• [9] Polymorphic oxidative metabolism of proguanil in a Nigerian population. Eur J Clin Pharmacol. 2002 Nov;58(8):543-5.
• [10] Application of higher throughput screening (HTS) inhibition assays to evaluate the interaction of antiparasitic drugs with cytochrome P450s. Drug Metab Dispos. 2001 Jan;29(1):30-5.
• [11] Cerner Multum, Inc. "UK Summary of Product Characteristics.".
• [12] Product Information. Xcopri (cenobamate). SK Life Science, Inc., Paramus, NJ.
• [13] Benoist G, van Oort I, et al "Drug-drug interaction potential in men treated with enzalutamide: Mind the gap." Br J Clin Pharmacol 0 (2017): epub. [PMID: 28881501]
• [14] Cerner Multum, Inc. "Australian Product Information.".