131707-24-9

Basic information

• Product Name: Ethyl 6-bromo-5-hydroxy-1-methyl-2-(phenylsulfanylmethyl)indole-3-carboxylate
• Synonyms: Si-5;Ethyl 6-bromo-5-hydroxy-1-methyl-2-[(phenylsulfanyl)methyl]-1H-indole-3-carboxylate;6-broMo-5-hydroxy-1-Methyl-2-phenyl S-Methyl indole-3-carboxylic acid ethyl ester;Ethyl 6-broMo-5-hydroxy-1-Methyl-2-((phenylthio)Methyl)-1H-Indole-3-carboxylate;6-Bromo-5-hydroxy-1-methyl-2-[(phenylthio)methyl]-1H-indole-3-carboxylic Acid Ethyl Ester;1-methyl-2-phenylthiomethyl-5-hydroxy-6-bromoindole -3- carboxy acid ethyl ester;ETHYL6-BROMO-6-HYDROXY-1-METHYL-2-((PHENYLTHIO)METHYL)IND.;ETHYL 6-BROMO-5-HYDROXY-1-METHYL-2-(PHENYLSULFANYLMETHYL)INDOLE-3-CARBOXYLATE
• CAS NO: 131707-24-9
• Molecular Formula: C₁₉H₁₈BrNO₃S
• Molecular Weight: 420.32
• EINECS: 1592732-453-0
• Mol File: 131707-24-9.mol
• Article Data: 9

Chemical Properties

• Boiling Point: 570.6 °C at 760 mmHg
• Flash Point: 298.9 °C
• Appearance: /
• Density: 1.44 g/cm³
• Vapor Pressure: 1.28E-13mmHg at 25°C
• Refractive Index: 1.64
• Storage Temp.: under inert gas (nitrogen or Argon) at 2-8°C
• Solubility: DMSO (Slightly), Methanol (Sparingly, Heated)
• PKA: 7.60±0.40(Predicted)
• CAS DataBase Reference: Ethyl 6-bromo-5-hydroxy-1-methyl-2-(phenylsulfanylmethyl)indole-3-carboxylate(CAS DataBase Reference)
• NIST Chemistry Reference: Ethyl 6-bromo-5-hydroxy-1-methyl-2-(phenylsulfanylmethyl)indole-3-carboxylate(131707-24-9)
• EPA Substance Registry System: Ethyl 6-bromo-5-hydroxy-1-methyl-2-(phenylsulfanylmethyl)indole-3-carboxylate(131707-24-9)

Safety Data

• HazardClass: IRRITANT
• Hazardous Substances Data: 131707-24-9(Hazardous Substances Data)

Usage

Uses

6-Bromo-5-hydroxy-1-methyl-2-[(phenylthio)methyl]-1H-indole-3-carboxylic Acid Ethyl Ester is used to prepare anti-hepatitis B virus activities of Et bromohydroxyindolecarboxylates.

InChI:InChI=1/C19H18BrNO3S/c1-3-24-19(23)18-13-9-17(22)14(20)10-15(13)21(2)16(18)11-25-12-7-5-4-6-8-12/h4-10,22H,3,11H2,1-2H3

Synthetic route

5-acetoxy-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid ethyl ester (110543-98-1) + thiophenol (108-98-5) → 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9)

Conditions	Yield
With potassium hydroxide In methanol for 3h; Ambient temperature;	96.4%
Stage #1: thiophenol With sodium hydroxide In methanol for 2h; Stage #2: 5-acetoxy-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid ethyl ester In methanol for 3h;	90.8%
Stage #1: 5-acetoxy-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid ethyl ester; thiophenol With sodium hydroxide In methanol at 15 - 20℃; for 1h; Stage #2: With acetic acid In methanol; acetone for 1h; Reflux;	88.6%

C14H13Br2NO4 + thiophenol (108-98-5) → 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9)

Conditions	Yield
With potassium hydroxide In methanol at 20℃; for 25h;	80.2%

arbidol (131707-25-0) → 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9)

Conditions	Yield
With 1H-imidazole In xylene Heating;	55%

1,2-dimethyl-5-acetoxy-1H-indole-3-carboxylic acid ethyl ester (40945-79-7) → 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: 87 percent / Br2 / CCl4 / 2 h / Heating 2: 96.4 percent / KOH / methanol / 3 h / Ambient temperature View Scheme
Multi-step reaction with 2 steps 1.1: dibenzoyl peroxide; bromine / chloroform / 3 h / Reflux 2.1: sodium hydroxide / methanol / 2 h 2.2: 3 h View Scheme
Multi-step reaction with 2 steps 1.1: bromine / tetrachloromethane / 16 h / Reflux; Inert atmosphere 2.1: potassium hydroxide / methanol / 0.25 h / 20 °C / Inert atmosphere 2.2: 3 h / Cooling with ice; Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1.1: bromine / tetrachloromethane / 16 h / Inert atmosphere; Reflux 2.1: potassium hydroxide / methanol / 0.25 h / 20 °C / Inert atmosphere 2.2: 3 h / Inert atmosphere; Cooling with ice View Scheme
Multi-step reaction with 2 steps 1.1: [RhCl2(p-cymene)]2; N-Bromosuccinimide / water; N,N-dimethyl acetamide / 24 h / 90 °C / Inert atmosphere 2.1: potassium hydroxide; methanol / 0.25 h / 20 °C 2.2: 4 h / 20 °C View Scheme

C14H17NO4 → 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: potassium carbonate; palladium diacetate; copper diacetate / N,N-dimethyl-formamide / 3 h / 80 °C 2.1: potassium carbonate / N,N-dimethyl-formamide / 6 h / 100 °C 3.1: dibenzoyl peroxide; bromine / chloroform / 3 h / Reflux 4.1: sodium hydroxide / methanol / 2 h 4.2: 3 h View Scheme

ethyl 5-acetyloxy-2-methyl-1H-indole-3-carboxylate (20862-91-3) → 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium carbonate / N,N-dimethyl-formamide / 6 h / 100 °C 2.1: dibenzoyl peroxide; bromine / chloroform / 3 h / Reflux 3.1: sodium hydroxide / methanol / 2 h 3.2: 3 h View Scheme
Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 1.5 h / Cooling with ice; Inert atmosphere 2.1: bromine / tetrachloromethane / 16 h / Reflux; Inert atmosphere 3.1: potassium hydroxide / methanol / 0.25 h / 20 °C / Inert atmosphere 3.2: 3 h / Cooling with ice; Inert atmosphere View Scheme
Multi-step reaction with 3 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 1.5 h / Inert atmosphere; Cooling with ice 2.1: bromine / tetrachloromethane / 16 h / Inert atmosphere; Reflux 3.1: potassium hydroxide / methanol / 0.25 h / 20 °C / Inert atmosphere 3.2: 3 h / Inert atmosphere; Cooling with ice View Scheme

4-nitro-phenol (100-02-7) → 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: pyridine / acetone / 4 h / 20 °C / Reflux 2.1: iron; ammonium chloride / ethanol; water / 2 h / Reflux 3.1: indium(III) bromide / dichloromethane / 3 h / Reflux 4.1: potassium carbonate; palladium diacetate; copper diacetate / N,N-dimethyl-formamide / 3 h / 80 °C 5.1: potassium carbonate / N,N-dimethyl-formamide / 6 h / 100 °C 6.1: dibenzoyl peroxide; bromine / chloroform / 3 h / Reflux 7.1: sodium hydroxide / methanol / 2 h 7.2: 3 h View Scheme

4-nitrophenol acetate (830-03-5) → 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: iron; ammonium chloride / ethanol; water / 2 h / Reflux 2.1: indium(III) bromide / dichloromethane / 3 h / Reflux 3.1: potassium carbonate; palladium diacetate; copper diacetate / N,N-dimethyl-formamide / 3 h / 80 °C 4.1: potassium carbonate / N,N-dimethyl-formamide / 6 h / 100 °C 5.1: dibenzoyl peroxide; bromine / chloroform / 3 h / Reflux 6.1: sodium hydroxide / methanol / 2 h 6.2: 3 h View Scheme

p-aminophenyl acetate (13871-68-6) → 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: indium(III) bromide / dichloromethane / 3 h / Reflux 2.1: potassium carbonate; palladium diacetate; copper diacetate / N,N-dimethyl-formamide / 3 h / 80 °C 3.1: potassium carbonate / N,N-dimethyl-formamide / 6 h / 100 °C 4.1: dibenzoyl peroxide; bromine / chloroform / 3 h / Reflux 5.1: sodium hydroxide / methanol / 2 h 5.2: 3 h View Scheme

ethyl 5-hydroxy-2-methylindole-3-carboxylate (7598-91-6) → 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: pyridine / 1 h / Inert atmosphere; Reflux 2.1: sodium hydride / N,N-dimethyl-formamide / 1.5 h / Cooling with ice; Inert atmosphere 3.1: bromine / tetrachloromethane / 16 h / Reflux; Inert atmosphere 4.1: potassium hydroxide / methanol / 0.25 h / 20 °C / Inert atmosphere 4.2: 3 h / Cooling with ice; Inert atmosphere View Scheme
Multi-step reaction with 4 steps 1.1: pyridine / 1 h / Inert atmosphere; Reflux 2.1: sodium hydride / N,N-dimethyl-formamide / 1.5 h / Inert atmosphere; Cooling with ice 3.1: bromine / tetrachloromethane / 16 h / Inert atmosphere; Reflux 4.1: potassium hydroxide / methanol / 0.25 h / 20 °C / Inert atmosphere 4.2: 3 h / Inert atmosphere; Cooling with ice View Scheme

ethyl 6-bromo-2-(bromomethyl)-5-hydroxy-1-methyl-1H-indole-3-carboxylate + thiophenol (108-98-5) → 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9)

Conditions	Yield
Stage #1: thiophenol With potassium hydroxide In methanol at 20℃; for 0.25h; Inert atmosphere; Stage #2: ethyl 6-bromo-2-(bromomethyl)-5-hydroxy-1-methyl-1H-indole-3-carboxylate In methanol; dichloromethane for 3h; Cooling with ice; Inert atmosphere;	362 mg

C14H15NO4 → 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: dibenzoyl peroxide; bromine / tetrachloromethane / 6 h / Reflux 2: potassium hydroxide / methanol / 25 h / 20 °C View Scheme

ethyl acetoacetate (141-97-9) → 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9)

Conditions	Yield
Multi-step reaction with 5 steps 1: water / 8 h / 20 °C 2: 1,2-dichloro-ethane / 12 h / 50 °C / Reflux 3: triethylamine / acetone / 6 h / 20 °C 4: dibenzoyl peroxide; bromine / tetrachloromethane / 6 h / Reflux 5: potassium hydroxide / methanol / 25 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: 3 h / 20 - 30 °C / Cooling with ice 2.1: zinc(II) chloride / dichloromethane / 4 h / 10 - 20 °C 3.1: sodium acetate / dichloromethane / 3 h / Reflux 4.1: hydrogen bromide; dihydrogen peroxide / 1,2-dichloro-ethane / 4.5 h / Reflux 5.1: sodium hydroxide / methanol / 1 h / 15 - 20 °C 5.2: 1 h / Reflux View Scheme

ethyl 3-methylaminocrotonate (870-85-9) → 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1,2-dichloro-ethane / 12 h / 50 °C / Reflux 2: triethylamine / acetone / 6 h / 20 °C 3: dibenzoyl peroxide; bromine / tetrachloromethane / 6 h / Reflux 4: potassium hydroxide / methanol / 25 h / 20 °C View Scheme

mecarbinate (15574-49-9) → 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: triethylamine / acetone / 6 h / 20 °C 2: dibenzoyl peroxide; bromine / tetrachloromethane / 6 h / Reflux 3: potassium hydroxide / methanol / 25 h / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: sodium acetate / dichloromethane / 3 h / Reflux 2.1: hydrogen bromide; dihydrogen peroxide / 1,2-dichloro-ethane / 4.5 h / Reflux 3.1: sodium hydroxide / methanol / 1 h / 15 - 20 °C 3.2: 1 h / Reflux View Scheme
Multi-step reaction with 3 steps 1.1: 4 h / Reflux 2.1: [RhCl2(p-cymene)]2; N-Bromosuccinimide / water; N,N-dimethyl acetamide / 24 h / 90 °C / Inert atmosphere 3.1: potassium hydroxide; methanol / 0.25 h / 20 °C 3.2: 4 h / 20 °C View Scheme

ethyl N-methyl β-aminocrotonate (65578-36-1) → 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: zinc(II) chloride / dichloromethane / 4 h / 10 - 20 °C 2.1: sodium acetate / dichloromethane / 3 h / Reflux 3.1: hydrogen bromide; dihydrogen peroxide / 1,2-dichloro-ethane / 4.5 h / Reflux 4.1: sodium hydroxide / methanol / 1 h / 15 - 20 °C 4.2: 1 h / Reflux View Scheme

6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9) + 2-bromoethanol (540-51-2) → C21H22BrNO4S

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 8h;	88.7%

formaldehyd (50-00-0) + dimethyl amine (124-40-3) + 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9) → Arbidol hydrochloride (131707-23-8)

Conditions	Yield
Stage #1: formaldehyd; dimethyl amine; 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester With aminosulfonic acid In water at 30 - 40℃; for 3h; Cooling with ice; Stage #2: With hydrogenchloride In water; acetone at 60℃; pH=1;	85.6%

formaldehyd (50-00-0) + dimethyl amine (124-40-3) + 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9) → arbidol (131707-25-0)

Conditions	Yield
With acetic acid In water at 65 - 75℃; for 0.5h;	85.1%
Stage #1: formaldehyd; dimethyl amine With acetic acid In water at 0℃; for 0.25h; Stage #2: 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester In water at 80℃; for 4h;	60%

6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9) → 1-methyl-2-phenylthiomethyl-3-ethoxycarbonyl-5-hydroxy-6-bromoindole sulfoxide

Conditions	Yield
With dihydrogen peroxide; acetic acid for 48h; Ambient temperature;	76.6%

bis-(dimethylamino)methane (51-80-9) + 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9) → arbidol (131707-25-0)

Conditions	Yield
In 1,4-dioxane for 3h; Heating;	70%
In 1,4-dioxane for 3.5h; Reflux; Inert atmosphere;	51%
Stage #1: bis-(dimethylamino)methane; 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester In 1,4-dioxane for 3.5h; Inert atmosphere; Reflux; Stage #2: With hydrogenchloride In water; ethyl acetate	51%

6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9) → 2-Benzenesulfinylmethyl-6-bromo-4-dimethylaminomethyl-5-hydroxy-1-methyl-1H-indole-3-carboxylic acid ethyl ester

Conditions	Yield
Multi-step reaction with 2 steps 1: 76.6 percent / 30percent H2O2, glacial AcOH / 48 h / Ambient temperature 2: dioxane / 4 h / Heating View Scheme

formaldehyd (50-00-0) + 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9) → arbidol (131707-25-0)

Conditions	Yield
With potassium hydroxide; acetic acid; dimethyl amine

6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9) → C29H36BrN3O5S

Conditions	Yield
Multi-step reaction with 2 steps 1: 1,4-dioxane / 3.5 h / Reflux; Inert atmosphere 2: 1,4-dioxane / Reflux; Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: 1,4-dioxane / 3.5 h / Inert atmosphere; Reflux 2: 1,4-dioxane / Inert atmosphere; Reflux View Scheme

6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9) → C26H32BrN3O4S

Conditions	Yield
Multi-step reaction with 2 steps 1: 1,4-dioxane / 3.5 h / Reflux; Inert atmosphere 2: 1,4-dioxane / Reflux; Inert atmosphere View Scheme
Multi-step reaction with 2 steps 1: 1,4-dioxane / 3.5 h / Inert atmosphere; Reflux 2: 1,4-dioxane / Inert atmosphere; Reflux View Scheme

6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9) → ethyl 6-methyl-7-(phenylthiomethyl)-2,3-dihydro-1,4-dioxino[2,3-f]indole-8-carboxylate

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / N,N-dimethyl-formamide / 8 h / 60 °C 2: caesium carbonate; 2'-(di-tert-butylphosphanyl)-N,N-dimethyl-[1,1'-biphenyl]-2-amine; palladium diacetate / toluene / 4 h / Reflux View Scheme

6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylic acid ethyl ester (131707-24-9) → ethyl 6-methyl-7-(phenylsulfinylmethyl)-2,3-dihydro-1,4-dioxin[2,3-f]indole-8-carboxylate

Conditions	Yield
Multi-step reaction with 3 steps 1: potassium carbonate / N,N-dimethyl-formamide / 8 h / 60 °C 2: caesium carbonate; 2'-(di-tert-butylphosphanyl)-N,N-dimethyl-[1,1'-biphenyl]-2-amine; palladium diacetate / toluene / 4 h / Reflux 3: 3-chloro-benzenecarboperoxoic acid / dichloromethane / 6 h / -20 °C View Scheme

Upstream product

• 40945-79-7 1,2-dimethyl-5-acetoxy-1H-indole-3-carboxylic acid ethyl ester 
• 7598-91-6 ethyl 5-hydroxy-2-methylindole-3-carboxylate 
• 108-98-5 thiophenol 
• 65578-36-1 ethyl N-methyl β-aminocrotonate 
• 15574-49-9 mecarbinate 
• 870-85-9 ethyl 3-methylaminocrotonate 
• 141-97-9 ethyl acetoacetate 
• 13871-68-6 p-aminophenyl acetate 
• 830-03-5 4-nitrophenol acetate 
• 100-02-7 4-nitro-phenol 
• 20862-91-3 ethyl 5-acetyloxy-2-methyl-1H-indole-3-carboxylate 
• 131707-25-0 arbidol 
• 110543-98-1 5-acetoxy-6-bromo-2-bromomethyl-1-methylindole-3-carboxylic acid ethyl ester 

Downstream Products

• 131707-25-0 arbidol 
• 131707-23-8 Arbidol hydrochloride 

Relevant articles and documents

Preparation method of arbidol intermediate

The invention discloses a preparation method of an arbidol intermediate. Ethyl acetoacetate, monomethylamine and p-benzoquinone used as initial raw materials undergo methylation, cyclization, acetylation, bromination and benzene vulcanization to prepare the target compound ethyl 5-hydroxy-6-bromo-2-phenylthiomethyl-1-methylindole-3-carboxylate. The preparation method of the arbidol intermediate issimple and convenient to operate, cheap and easily available in raw materials, high in yield, low in cost, good in quality, environment-friendly, mild in reaction condition, high in safety productioncoefficient and suitable for large-scale industrial production.

5,6-indole dioxane derivatives and preparation method and application thereof

The invention belongs to the field of drug synthesis, and particularly relates to a 5,6-indolo dioxane derivative and a preparation method and application thereof. The invention provides the 5,6-indolo dioxane derivative and the preparation method and application thereof. The derivative has certain inhibiting effect on HBV and low toxicity, and is expected to be further used for development of drugs for treating diseases caused by HBV infection, especially for preparing of drugs for treating and preventing viral hepatitis B.

Structure-based optimization and synthesis of antiviral drug Arbidol analogues with significantly improved affinity to influenza hemagglutinin

Influenza is a highly contagious respiratory viral infection responsible for up to 50,000 deaths per annum in the US alone. The need for new therapeutics with novel modes of action is of paramount importance. We determined the X-ray structure of Arbidol with influenza hemagglutinin and found it was located in a distinct binding pocket. Herein, we report a structure-activity relationship study based on the co-complex combined with bio-layer interferometry to assess the binding of our compounds. Addition of a meta-hydroxy group to the thiophenol moiety of Arbidol to replace a structured water molecule in the binding pocket resulted in a dramatic increase in affinity against both H3 (1150-fold) and H1 (98-fold) hemagglutinin subtypes. Our analogues represent novel leads to yield more potent compounds against hemagglutinin that block viral entry.