Structure Activity Relationship

Capuramycin analog SQ-641 (Fig. 27; 19b) has shown moderate activity against MTb. From SAR studies, the uridine unit and the protic amide are essential for

O ch3 o

H3 h2n-

HO"

N NH

Caprazamycins A-G 18a-g

Fig. 26 Caprazamycins A-G

18a R 18b R

r>o VNH

Capuramycin 19a

HO OH

CONH2

r>o VNH

Capuramycin 19a

H3C0 Yc9H16

H3C0 Yc9H16

yy ho oh

19c R1 = C0R2, R2 = 0C13H27 19d R1 = C0R2, R2 = 0C1BHg7 19e Ri = COR2, R2 = NHalkyl

19f R2 = n-Bu; CPZEN-45 19g R2 = n-Hex 19h R2 = 0C6H13

HO OH

Fig. 27 Capuramycin and analogs SQ-641 and CPZEN-45

Fig. 28 SARfor capuramycins

Protic amide required

" 0R1

H3C0

C0NH2

" 0R1

— Uridine unit essential

H3C0

R1 = lipophilic for better uptake bactericidal activity (Fig. 28) [289]. At the R2 position in Fig. 28, lipophilic groups, including medium size alkyl chains, phenethyl, and phenyl-type substitutions, retained moderate activity but benzyl-type substitution showed decreased activity. When different lipophilic groups were placed at the R1 position, installation of a decanoate substituent showed the largest increase in whole cell activity compared to shorter alkanoate chains, likely due to the increased lipophilicity, which (see Sect. 5.1) increases intracellular uptake into MTb.

CPZEN-45 (Fig. 27; 19f), a caprazamycin analog, is shown in Fig. 27. SAR studies revealed that the uridine and the aminoribose are crucial for antibacterial activity [290]. Initially, installation of ester substituents at R1 with R2 alkyl chains showed that tridecane (C13H27, Fig. 27; 19c) and octadecane (C18H37, Fig. 27; 19d) esters showed equipotent activity, whereas a 21-carbon chain with unsaturation at C(18) showed decreased potency. Next, the effect of the amide substituent R2 (19e) was investigated, which showed that the potency generally increased up to a 21 carbon alkyl chain and exhibited decreased potency with even longer alkyl sub-stituents. Finally, anilinoamide substituents with n-butyl (CPZEN-45, Fig. 27; 19f), n-hexyl (Fig. 27; 19g), and hexyloxy (Fig. 27; 19h) showed the most potent activity against MTb. Highly lipophilic molecules are, of course, not good candidates for lead optimization programs; thus a considerable amount of work is still required to discover better candidates from CPZEN-45 (19f) as leads for drug development.

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