Azole-based inhibitors of P.

falciparum LDH

Supplementary Material

Synthesis of Derivatives of Parent Azole Compounds

In order to establish a structure-activity relationship (SAR) for the azole family, a wide

range of derivatives were prepared. The parent compounds (hydroxyacid azoles) and their

hydroxyesters derivatives from the oxadiazole (OXD1) and isoxazole groups (IOA1-

IOA3, IOA6 and IOA8), were prepared using the methods previously described in the

literature, with slight modifications to facilitate gram scale process (see references in

Table S1). The compoundsfrom the thiadiazole (TDA1 - TDA2) and triazole groups

(TRZ1-TRZ5), were acquired from external sources for screening purposes. The

experimental procedures for the synthesis of novel compounds described in the text, and

their correspond ing NMR spectral data, are described below.

S1.1: 4-hydroxy-1,2,5-oxadiazole-3-carboxylic acid, ethyl ester (OXD7)

A solution of 1.70 g 4-hydroxy-1,2,5-oxadiazole-3-carboxylic acid (OXD1) (13 mmol) in

30 ml of ethanol in the presence of catalytic amounts of H2 SO4 (300µL), was heated to

reflux. The progress of the reaction was monitored by HPLC. After 8 hours of heating, the

starting material was consumed. The reaction mixture was cooled to room temperature and

the solvent was removed under reduce pressure. The mixture was re-dissolved in water

(pH of the solution = 11) and extracted with Et2 O to remove any non acidic residue

1
 Azole-based inhibitors of P. falciparum LDH

formed in the reaction. The aqueous phase was acidified to pH=1 using concentrated HCl

and then extracted with Et2 O. The combined ether extracts were washed with brine and the

solvent removed under reduce pressure to yield 1.04 g of the expected compound as a

white solid (Yield 50%). 1 H-RMN (DMSO, δ): 1.30 (t, J=7.15, 3H), 4.36 (q, J=7.15, 2H),

13.4 (bs, 1H, OH). 13 C-RMN (DMSO, δ): 14.0, 62.3, 140.5, 157.34, 162.8.

S1.2: 4-hydroxy-1,2,5-oxadiazole-3-carboxilic acid, (3',4'-dichloro)benzyl ester

(OXD6 )

A solution was prepared from 272 mg of 4-hydroxy-1,2,5-oxadiazole-3-carboxylic acid

(OXD1) in 3 ml of DMF, to which were successively added 31 mg of dimethyl

aminopyridine (0.25 mmol), 370 mg of 3,4-dichlorobenzyl alcohol (2.1 mmol), 1.07 g

(2.25 mmol) of methyl-p-toluenesulphonate and 354 mg of N-cyclohexyl-N’-(2-

morpholinoethyl)carbodiimide. The progression of the reaction was monitored by TLC.

After 3H of reaction no starting material was detected. The precipitant formed during the

reaction was filtered, and the mother liquor was concentrated under reduced pressure,

obtaining a thick melange that was re-dissolved in EtOAc and extracted with NH4 Cl (1N).

The combined organic extracts were washed with brine, dried over Na2 SO4 , and

concentrated under reduced pressure. The yellowish residue obtained was purified by flash

chromatography using AcOEt:Hexane (1:1), which was further purified by

recrystallisation with ethyl ether: hexane. Finally 150 mg of the pure expected compound

was obtained in a 24% yield of a white crystalline solid. 1H-RMN (DMSO, δ): 5.29 (s,

2
 Azole-based inhibitors of P. falciparum LDH

2H), 7.44 (d, 1H, J=8.25), 7.65 (d, 1H, J=8.25), 7.73 (s, 1H). 13 C-RMN (DMSO δ): 64.3,

128.1, 129.8, 130.7, 130.6, 131.0, 137.0, 142.5, 160.7, 168.2

S1.3: 3-hydroxy-5-methyl-4-isoxazolecarboxilic acid, ethyl ester (IOA7)

A solution of 3.89 g hydroxyl amine hydrochloride (56 mmol) in 25 ml of methanol was

cooled to 0ºC and, under stirring, 20 ml of MeONa (30% in MeOH) were slowly added.

The formation of an abundant white precipitate (NaCl) was observed during the

neutralisation. Then, 11 g of ethyl dimethyl (1-ethoxyethylidene) malonate 1 (51 mmol)

dissolved in 100 ml of methanol were added to the reaction media. After 25 min of

reaction no starting material could be detected by TLC. The product was purified by

initially filtering the NaCl formed, and removing the methanol used as solvent under

reduced pressure. The brown mixture obtained was redissolved in a 1:1 mixture of ethyl

acetate and NH4 Cl, and the phases were separated. The organic phase was conserved and

the aqueous layer was treated with concentrated HCl to adjust the pH to pH=4. The

mixture was further extracted with ethyl acetate (3x200 ml) to remove any traces of the

isomer from the media. The combined organic extracts were collected, washed with brine,

dried over Na2 SO4 and evaporated under reduced pressure to yield a mixture that

contained the major isomer, which was purified by crystallisation from methanol to yield

45% of IOA7. 1 H-RMN (DMSO, δ): 2.52 (t, s, 3H), 3.73 (s, 3H). 13 C-RMN (CD3 OD, δ):

14.6, 61.2, 88.3, 152.5, 163.1, 172.1 The corresponding data are given below. The

aqueous phase that was originally adjusted to pH=4 contained the minor isomer, which

3
 Azole-based inhibitors of P. falciparum LDH

was isolated in 37% yield after acidification to pH=1: IOA3e: 1 H-RMN (DMSO, δ): 2.28

(t, s, 3H), 3.62 (s, 3H).

Synthesis of ether-derivatives of parent compounds:

All ethers were synthesised from the ethyl esters of the corresponding parent compounds.

The synthesis of each compound required two steps: first, the introduction of the

substituent in the hydroxyl functional group, and secondly the saponification of the ester

group to yield the corresponding acid.

S1.4: 3-methoxy-4-isoxazolecarboxilic acid, ethyl ester (IOA5e)

Using an oven-dried two-neck flask equipped with a reflux condenser and flushed with N2

after the addition of 2.5g of Cs2 CO3 (3.81 mmol), a solution of IOA6 (600 mg, 3.81

mmol) in 10 ml of acetone was added to the base and the heterogeneous mixture was

stirred and heated at 60ºC over one hour (release of CO2 was observed during the

generation of the anion). After this period, the mixture was left to reach room temperature

and 356 ul of MeI (5.72 mmol) was added, and the mixture was stirred for an additional

hour. The progress of the reaction was monitored by TLC. After 1 hour at the same

temperature all the starting material had been consumed. The expected compound was

isolated by addition of 20 ml of saturated NH4 Cl and extracted with ethyl ether (3x50

mL). The combined organic extracts were washed in brine, dried over MgSO4 and the

solvent was evaporated under reduced pressure. The crude obtained was purified by flash

4
 Azole-based inhibitors of P. falciparum LDH

chromatography (Hexane: AcOEt, 9:1), to yield the expected compound in 64% yield. 1 H-

NMR (CDCl3, δ): 1.33 (t, J=7.14, 3H), 4.31(s, 3H), 4.31, (q, J=7.14, 2H), 8.67 (s, 1H).

13
C-NMR (CDCl3, δ): 14.2, 57.9, 61.0, 105.2, 160.2, 164.6, 169.4

S1.5: N-methyl-3-oxo-2(2H)-4-isoxazolecarboxilic acid, ethyl ester IOA4e

In a dried oven flask, flushed with N2 and under inert atmosphere (N 2 ), was placed a

solution of IOA6 (300 mg , 1.9 mmol) in 5ml of dry dichloromethane. The solution was

cooled to 0ºC and 1.9 mL of TMSCHN 2 (3.81 mmol of 2M solution in hexane) was added

drop-wise to the mixture. The release of N2 was observed during the reaction. The

progress of the reaction was monitored by TLC and after 10 min of reaction no starting

material was detected. The reaction was stopped by evaporation of the solvent under

reduced pressure and the crude directly purified by flash chromatography (Hex: AcOEt,

10:1). The expected compound was isolated as the less polar compound in a 45% yield.
1
H-NMR (CDCl3, δ): 1.33 (t, J=7.14, 3H), 3.55 (s, 3H), 4.31, (q, J=7.14, 2H), 8.42 (s, 1H).

13
C-NMR (CDCl3, δ): 14.2, 32.9, 61.1, 108.6, 160.2, 163.0, 175.4

S1.6: General method A: Synthesis of ether derivatives under Mitsunobu conditions

Over a solution of 4-hydroxy-1,2,5-oxadiazole-3-carboxylate ethyl ester (OXD7) in

anhydrous THF and under N2 atmosphere, 1.04 molar equivalents of PPh3 were added.

The reaction mixture was cooled to 0ºC, before the consecutive addition of 1 molar

equivalent of diethyl azadicarboxylate and 1 molar equivalent of the corresponding

5
 Azole-based inhibitors of P. falciparum LDH

alcohol. After addition of the alcohol the cooling bath was removed and the reaction

mixture was left stirring overnight. The solvent was removed under reduced pressure. The

crude obtained was washed with hexane and the remaining solid was directly purified by

flash chromatography using the eluent indicated in each case.

S1.7: 4-[(3-phenylprop-2-enyl)-oxi]-1,2,5-oxadiazole-3-carboxylic acid, ethyl ester

(OXD8e)

This compound was prepared following the general method A starting from 119 mg of

OXD7 (0.75 mmol) and 100 mg of the 3-phenyl-2-propen-1-ol (cinnamyl alcohol, 0.75

mmol) and the corresponding amounts of PPh3 (273mg, 0.78 mmol) and DEAD (130 mg,

0.75 mmol). The crude from the reaction mixture was purified by flash chromatography,

using a gradient from AcOEt: Hex (1:10) to pure AcOEt. Yield 42%. 1 H-NMR (CDCl3 δ):

1.45 (t, J=7.13, 3H), 4.48 (q, J=7.14, 2H), 5.07 (dd, J1 =6.54, J2 =1.28, 2H), 6.45 (dt,

J1 =15.93, J2 =6.40, J3 =6.40, 1H), 6.83 (d, J=15.74, 1H), 7.29-7.44 (m, 5H).

S1.8: 4-[(p-methoxyphenyl)-methoxy]-1,2,5-oxadiazole-3-carboxilic acid, ethyl ester

(OXD9e).

OXD9e was prepared following the general method A starting from 150 mg of OXD7

(0.95 mmol) and 133 mg of 4- methoxy benzyl alcohol (0.95 mmol) and the corresponding

amounts of PPh3 (343mg, 0.99 mmol) and DEAD (165 mg, 0.95 mmol). The crude from

the reaction mixture was purified by flash chromatography, using a gradient from AcOEt:

6
 Azole-based inhibitors of P. falciparum LDH

Hex (1:3) to pure AcOEt. Yield 49%. 1 H-NMR (CDCl3, δ): 1.40 (t, J=7.14, 3H), 3.82(s,

3H), 4.44, (q, J=7.14, 2H), 5.36 (s, 2H), 6.92, (d, J= 8.8, 2H), 7.43, (d, J= 8.8, 2H). 13 C-

NMR (CDCl3, δ): 14.0, 55.3, 62.3, 74.4, 114.0, 126.3, 130.4, 139.6, 157.2, 160.2, 163.8 .

S1.9: General Method B. Hydrolysis of hydroxyesters.

Over a cooled (0ºC) solution of the starting hydroxyester in methanol (2M solution), 4

equivalents of LiOH (1.25 N) were slowly added while stirring and the mixture was left to

reach room temperature on its own. The reaction was monitored by TLC, and usually a

period of 40 to 60 min was enough to complete the hydrolysis. The isolation procedure

was performed by removal of the methanol under reduced pressure, extraction with

dichloromethane to remove any organic component and acidification to pH=1. The

precipitate formed was filtered as the pure acid. When a significant precipitate was not

formed after acidification, the aqueous phase was extracted several times with AcOEt

(3x50 ml). The organic extracts were combined, washed with brine and dried over

Na2 SO4 . The expected compounds were obtained as pure compounds and usually did not

require any further purification.

S1.10: N-methyl-3-oxo-2(2H)-4-isoxazolecarboxilic acid, IOA4

Following the general procedure C, 87 mg of the ester N-methyl-3-oxo-2(2H)-4-

isoxazolecarboxilic acid (IOA4e) (0.31 mmol) were hyd rolysed over 90 minutes. A

further chromatographic purification was necessary (Hex: AcoEt (3:1) to AcOEt) to obtain

7
 Azole-based inhibitors of P. falciparum LDH

38 mg of the pure expected compound in 60% yield. 1 H-NMR (DMSO, δ): 2.93 (s, 3H),

9.09 (s, 1H), 13.0 (s, 1H). 13 C-NMR (DMSO, δ): 33.6, 108.1, 160.3, 167.0, 171.3 .

S1.11: 3-methoxy-4-isoxazolecarboxilic acid, ethyl ester IOA5

Following the general procedure B, 87 mg of the ester 3- methoxy-4-isoxazolecarboxilic

acid, ethyl ester (IOA5e) (0.31 mmol), were hydrolysed over 90 minutes. A furthe r

chromatographic purification was necessary (Hex: AcoEt (3:1) to AcOEt) to obtain 38 mg

of the pure expected compound in 60% yield. 1 H-NMR (DMSO, δ): 3.93 (s, 3H), 9.29 (s,

1H), 13.0 (s, 1H). 13 C-NMR (DMSO, δ): 57.5, 105.0, 160.9, 166.7, 169.1

S1.12: 4-[(3-phenylprop-2-enyl)-oxy]-1,2,5-oxadiazole-3-carboxylic acid (OXD8)

Following the general procedure B, 44 mg of 4-[(3-phenylprop-2-enyl)-oxy]-1,2,5-

oxadiazole-3-carboxylic acid, ethyl ester (OXD8e) (0.16 mmol), were hydrolysed over 90

min in a 64% yield. 1 H-RMN (CD3 OD δ): 5.04 (dd, J1 =6.42, J2 =1.29, 2H), 6.50 (dt,

J1 =15.94, J2 =6.42, J3 =6.42, 1H), 6.85 (d, J=15.94, 1H), 7.25-7.47 (m, 5H). 13 C-RMN

(CD3 OD, δ): 74.4, 122.9, 127.8, 129.4(4xC), 129.7 (4xC), 136.9, 137.5, 141.7, 159.8,

165.3.

S1.13: 4-[(p-methoxybenzyl)-oxy]-1,2,5-oxadiazole-3-carboxylic acid (OXD9)

8
 Azole-based inhibitors of P. falciparum LDH

Following the general procedure B, 87 mg of the ester 4-[(p- methoxybenzyl)-oxy]-1,2,5-

oxadiazole-3-carboxylic acid, ethyl ester (IOA9) (0.31 mmol), were hydrolysed over 90

minutes. A further chromatographic purification was necessary (Hex: AcoEt (3:1) to

AcOEt) to obtain 38 mg of the pure expected compound in 60% yield. 1 H-RMN (DMSO,

δ): 5.37 (s, 2H), 3.81 (s, 3H), 6.92, (d, J= 8.8, 2H), 7.44, (d, J= 8.8, 2H). 13 C-RMN

(DMSO, δ):55.3, 74.4, 113.0 (4xC), 126.5, 129.4 (4xC), 139.9, 157.5, 160.3, 165.8.

S1.14: 4-methoxy-1,2,5-tiadiazol-3-carboxylic acid (TDA3) 2.

Following the general procedure C, 44 mg of ethyl 4- methoxy-1,2,5-tiadiazol-3-

carboxylic acid ethyl ester (TDA3e) (0.16 mmol), were hydrolysed over 90 min in a 60%

yield with a purity >95% (HPLC). 1 H-RMN (CD3 OD, δ): 4.13 (s, 3H). 13 C-RMN (CD3 OD,

δ): 58.6, 140.9, 161.8, 167.2.

Synthesis of Bioisoster derivatives: Replacement of the carboxylic acid functional

group

S1.15: 4-(hydroxy-1,2,5-oxadiazole-3-oxo)- N-methylsulphonamide (OXD10)

To an oven-dried flask, flushed with N2 and containing 3Å molecular sieves, were added

182 mg of 4-hydroxy-1,2,5-oxadiazole-3-carboxylic acid (OXD1) (1.4 mmol) dissolved in

20 ml of dry THF, and 563 mg of 1,1' carbonyl diimidazole. The mixture was heated to 65

9
 Azole-based inhibitors of P. falciparum LDH

ºC and left stirring for 4 hours. After this period the mixture was cooled to room

temperature and 362 uL of methyl sulphonamide (3.5 mmol) and 524 µL of 1,8-

diazabycyclo-[5,4,0]-7-undecene (3.5 mmol) were added. The mixture was heated again to

65ºC overnight. After this period, the crude was diluted with ethyl acetate and filtered over

Celite®. The Celite ® was carefully washed with AcOEt and methano l until all of the

substrate had been eluted from the silica (TLC). The combined organic extracts were dried

over Na2 SO4 , and the solvent removed under reduced pressure. The oily residue obtained

was further purified by flash chromatography to isolate a ma in fraction that contained the

expected compound together with the amine used as base. This mixture was redissolved in

HCl (1N) and extracted with ACOEt (2x100 mL). The aqueous phase was discarded. The

organic solvent was removed under reduced pressure and the expected compound was

finally isolated as the lithium salt by treatment with a basic solution of NaOH (pH=6-7)

and subsequent lyophilisation. The sulphonamide OXD10 was obtained with >90% purity

(HPLC) in a 67% yield.

1
H-RMN (D2 O δ): 3.02 (s, 3H). 13 C-RMN (CD3 OD δ): 40.1, 145.3, 164.7, 165.5

S1.16: N-(3-hidroxy isoxazole-4-oxo)-methylsulphonamide (IOA9)

To an oven-dried flask, flushed with N2 and containing 3Å molecular sieves, were added

138 mg of 3-hydroxy- isooxazole-4-carboxylic acid (1.07 mmol) dissolved in 6 mL of dry

THF, and 563 mg of 1,1' carbonyl diimidazole. The mixture was heated at 70 ºC and left

stirring for 2 hours. After this period the mixture was cooled to room temperature and 204

mg of methyl sulphonamide (2.14 mmol) and 326mg of 1,8-diazabycyclo-[5,4,0]-7-

10
 Azole-based inhibitors of P. falciparum LDH

undecene (2.14 mmol) were added. The mixture was then heated to 65ºC overnight. After

this period the solvent was removed under reduced pressure and the oily residue was

partitioned in dichloromethane and NH4 Cl (1N). The aqueous phase was acidified to pH=

3 and then extracted with AcOEt (4x75ml). The different organic extracts were collected,

dried over Na2 SO4 and the solvent was removed under reduced pressure to yield a

yellowish residue that was macerated with acetonitrile to yield 20 mg of a white solid with

purity > 95 % (HPLC) in a 10% yield. The yield of the reaction was not improved since

the compound was used just for screening purposes. 1 H-RMN (CD3 OD, δ): 3.34 (s, 3H,

9.03 (s, 1H). 13 C-RMN (CD3 OD δ): 41.7, 107.2, 160.5, 166.2, 168.4

S1.17: 3-hydroxyisoxazol-4-hydroxymethyl amide (IOA10)

To an oven-dried flask, flushed with N2, were added 140mg of 3-hydroxy- isooxazole-4-

carboxylic acid (1.08 mmol) and 2 mL of thionyl chloride. The mixture was heated at

reflux under stirring for 3 hours. After this period the mixture was concentrated at reduced

pressure and the residue containing the corresponding acid chloride was redissolved in

anhydrous THF (5mL). This solution was added while stirring to a cooled (0ºC) solution

of 360 mg of methyl hydroxylamine (4.4 mmol) and 900 uL of triethylamine (6.5 mmol)

in 5ml of dry THF. The reaction mixture was then left to reach room temperature and

stirred overnight. The expected compound was isolated by acidification of the reaction

mixture with HCl (1N) and extraction with dichloromethane (3x50mL). The organic

extracts were combined, washed with brine and dried over Na2 SO4 . The solvent was

removed under reduced pressure to obtain a solid that was purified by flash

11
 Azole-based inhibitors of P. falciparum LDH

chromatography (dichloromethane:MeOH, 95:5) to obtain the expected bioisostere in a

30% yield with a purity >95% (HPLC). 1 H-RMN (CD3 OD, δ): 3.34 (s, 3H, CH3 ), 8.95 (s,

1H, CH). 13 C-RMN (CD3 OD δ): 36.2, 102.7, 163.8, 164.2, 171.7.

12
 Azole-based inhibitors of P. falciparum LDH

Bibliographic information on compounds prepared and cited in the article

Table S1A: Synthesis of 1,2,5-oxadiazole (OXD) series

Compound Structure Reference for synthesis

H. Wieland, Z. Kitasato and S. Utzino. Liebigs Ann. Chem. 478 (1930), p. 43

O
HO
OXD1 OH
N N
O

O
Strelenko, Yu. A.; Sheremetev, A. B.; Khmel'nickii, L. I. Monosubstituted
H 2N
OH
OXD2 N N furazans. I. NMR investigations. Khimiya Geterotsiklicheskikh Soedinenii
O

(1992), (8), 1101-5.

Purchased from external sources: Synthesis details not available

H HO
N O
HO
OXD3 N N
O

O Bought from external sources: Catalog Name: Chemical Block Building Blocks
OH
OXD4 N N Registry Number: 88598-08-7 , CHEMCATS
O

13
 Azole-based inhibitors of P. falciparum LDH
O H. Wieland, Z. Kitasato and S. Utzino. Liebigs Ann. Chem. 478 (1930), p. 43
HO
OH
OXD5 N N
O
O Described in Section S1.2
HO Cl
O
OXD6 N N
O Cl

O Willson, Timothy M.; Charifson, Paul S.; Baxter, Anthony D.; Geddie, Nora G.
HO
OEt
N N
Bone targeted drugs. 1. Identification of heterocycles with hydroxyapatite affinity.
OXD7 O
Bioorganic & Medicinal Chemistry Letters (1996), 6(9), 1043-1046. Also

described in Section 1.8.

O
Described in Section S1.6, S1.12
O
OH
OXD8
N N
O

O
O Described in Section S1.8, S1.9, S1.13
O

OXD9 N
O
N

14
 Azole-based inhibitors of P. falciparum LDH
H O Described in Section S1.15
O N
S
Me
O
OXD10 HO
N
N O

15
 Azole-based inhibitors of P. falciparum LDH
Table S1B: Synthesis of 1,2/1,5-isoxazole (IOA) series:

Compound Structure Reference

O Willson, Timothy M.; Charifson, Paul S.; Baxter, Antho ny D.; Geddie, Nora G. Bone targeted
IOA1 HO
OH
N drugs. 1. Identification of heterocycles with hydroxyapatite affinity. Bioorganic & Medicinal
O
Chemistry Letters (1996), 6(9), 1043-1046

O Willson, Timothy M.; Charifson, Paul S.; Baxter, Anthony D.; Geddie, Nora G. Bone targeted
HO
IOA2 OH
N drugs. 1. Identification of heterocycles with hydroxyapatite affinity. Bioorganic & Medicinal
O
Chemistry Letters (1996), 6(9), 1043-1046

O Von Itter, Franz Albert; Steffen, Kla us Dieter. Preparation of dialkyl

IOA3 HO
OH
alkoxyalkylidenemalonates by aluminosilicate-catalyzed condensation of dialkyl malonates
N
O
with ortho esters. Eur. Pat. Appl. (1991), 6 pp. EP 413918

O Described in Section S1.5, S1.10

IOA4 O
OH
N
H3C O

16
 Azole-based inhibitors of P. falciparum LDH
O Described in Section S1.4, S1.11
IOA5 O
H3C OH
N
O

O Willson, Timothy M.; Charifson, Paul S.; Baxter, Anthony D.; Geddie, Nora G. Bone targeted
HO
IOA6
OEt drugs. 1. Identification of heterocycles with hydroxyapatite affinity. Bioorganic & Medicinal
N
O Chemistry Letters (1996), 6(9), 1043-1046

O Von Itter, Franz Albert; Steffen, Klaus Dieter. Preparation of dialkyl

HO OMe
IOA7 alkoxyalkylidenemalonates by aluminosilicate-catalyzed condensation of dialkyl malonates
O CH3
N with ortho esters. Eur. Pat. Appl. (1991), 6 pp. EP 413918. Modified as described in

Section S1.3

O Willson, Timothy M.; Charifson, Paul S.; Baxter, Anthony D.; Geddie, Nora G. Bone targeted
IOA8 HO OEt
drugs. 1. Ident ification of heterocycles with hydroxyapatite affinity. Bioorganic & Medicinal
O
N
Chemistry Letters (1996), 6(9), 1043-1046

O
HO
IOA9
N Described in Section S1.17
N S O
O O Me

17
 Azole-based inhibitors of P. falciparum LDH
Me Described in Section S1.18
IOA10 O N
OH

HO

N O

18
 Azole-based inhibitors of P. falciparum LDH

Table S1C: Synthesis of 1,2,5-thiadiazole (TDA) series:

Compound Structure Reference

O J.M. Ross and W.C. Smith. J. Am. Chem. Soc. 86 (1964), p. 2861
TDA1 HO
OH

N N
S

O Bought form external sources: Interchim Intermediates. Registry Number: 2829-58-5

H2N
OH
TDA2 Meyer, Rich B., Jr.; Skibo, Edward B. Synthesis of fused [1,2,6] thiadiazine 1,1-dioxides as
N N
S potential transition-state analog inhibitors of xanthine oxidase and guanase. Journal of

Medicinal Chemistry (1979), 22(8), 944-8.

O J.M. Ross and W.C. Smith. J. Am. Chem. Soc. 86 (1964), p. 2861
TDA3 H3C O OH
Modified as described in Section 1.14
N N
S

19
 Azole-based inhibitors of P. falciparum LDH

Table S1D: Synthesis of Triazole (TRZ) series

Compound Structure Reference

TRZ1 O Screening Compound but the synthesis is described in: Y. A. Rozin, E. A. Saveleva, Y. Y.
HO
OH
N N Morzherin, W, Dehaen, S. Toppet, L. Van Meervelt, V. A. Bakulev, J. Chem. Soc, Perkin
N

Transactions 1, 2002, 2, 211-216.

O
TRZ2 GSK Screening Compound
HO
OH
N N
N

TRZ3 HO D. R. Buckle, C. J. M. Rockell, J. Chem Soc, Perkin I, 1982, 627-63.

HO
O
N N Ph
N

TRZ4 O D. R. Buckle, C. J. M. Rockell, J. Chem Soc, Perkin I, 1982, 627-63.

HO
OH
N N
N

Ph

TRZ5 N Scifinder Search: Katritzky, Alan R.; Zhang, Yuming; Singh, Sandeep K. 1,2,3-triazole
O
N
N
HO H formation under mild conditions via 1,3-dipolar cycloaddition of acetylenes with azides.

21
 Azole-based inhibitors of P. falciparum LDH
Heterocycles (2003), 60(5), 1225-1239.

22