Shibata S, Gillespie JR, Ranade RM, Koh CY, Kim JE, Laydbak JU, Zucker FH, Hol WGJ, Verlinde CLMJ, Buckner FS, Fan EJ. have previously reported on low-cost dialkylimidazole compounds that kill amastigotes in the low nM range.5 The activity of these compounds is due to inhibition of the enzyme sterol 14-demethylase6 (CYP51), essential for the biosynthesis of ergosterol-like sterols, crucial components of the parasite membrane.7 In the acute mouse model of Chagas disease, several dialkylimidazole compounds reduced parasitemia to microscopically undetectable levels after oral administration.5, 8 However, the compounds are relatively large, hence we attempted to reduce the size of our original lead 2 while maintaining potency to arrive at inhibitors like 3 with more drug-like physicochemical properties. Open in a separate window Physique 1 Most potent Sterol-14alpha demethylase inhibitors We previously reported a very simple and straightforward synthetic route to arrive at dialkylimidazoles in good yields.5 Synthesis requires the preparation of two fragments that are then coupled under reductive amination conditions. Analogs 12a-l were obtained according to Scheme 1. To generate the first fragment, trityl guarded imidazole carboxaldehyde 5 was treated with substituted benzylbromides and subsequent deprotection resulted in substituted imidazole carboxaldehyde 6 in moderate to good yields varied depending on substituents on alkyl bromide. The second fragment 11 was derived from 7 using reported methods.5 Reductive IRAK inhibitor 1 coupling of key intermediates 11 and 6 provided the target compounds 12a-l. Open in a separate window Scheme 1 Synthesis of dialkylimidazole analogs a Preparation of analogs 12r-v is usually described in Scheme 2. Phenol derivatives 15 were reacted with alcohols in presence of DIAD and TPP in THF to generate 16 in approximately 45-50% yields. The intermediates were converted to the target compounds using the procedure described in Scheme 1. Synthesis of halogenated dialkylimidazole derivatives is usually depicted in Schemes 3 and ?and4.4. Compound 21 was synthesized as Mouse Monoclonal to KT3 tag a versatile intermediate for the preparation of several analogs in this study. It was obtained inconsiderable yield from 18 by Suzuki coupling followed by bromination and further alkylation with 5. Open in a separate window Scheme 2 Preparation of dialkylimidazoles made up of 2-ethoxy-morpholines and piperidinesa Open in a separate window Scheme 3 Preparation of halogenated dialkylimidazoles a Open in a separate window Scheme 4 Synthetic strategy for dialkylimidazole analogs bearing -NH2 at Ra The second fragment was readily prepared from available nitro derivatives. Fragments were coupled to generate the target compounds 24a-r in moderate to good yields. Similarly, all amino analogues were prepared as described in Scheme 4. In our previous studies, inhibitors were potent but large and highly hydrophobic6. Hence we decided to produce simplified and more drug-like analogues with reduced molecular weight and lipophilicity (Table 1). We generated new structures by modifying 2 at four positions R, R1, R2 and R3 (Physique 1). All the synthesized analogs were tested against the clinically relevant amastigote stages of amastigotes EC50(nM)position around the terminal phenyl (R3) such as hydroxy and methoxy and had little effect on potency. However, the introduction of an amino group at the 4-position on R3 (12k) dramatically inhibited the cultures at low nanomolar level with 10\fold increase in potency (EC50=1.6 nM) compared with compound 12. Previously explored SAR of the benzothiazole moiety 6 suggested that benzothiazole is at the periphery of the active site, partially exposed to solvent. Replacing it by a simple chloro retains the potency against and, importantly, reduces the molecular mass by 100.6 By retaining ?Cl at R2 position, we obtained an extra molecular mass windows within Lipinski space to explore R3 with a variety of heterocyclic as well as saturated heterocyclic systems (12n-q). However, associated modifications did not improve potency. In addition, alternative of the benzothiazole moiety at R2 with alkoxy and alkylamino linked heterocycles, (12r-v), displayed as much as a 10\fold drop in potency. These analogues suggest a limited tolerance at R3 for further modifications containing large, flexible linked heterocycles. Considering the.To generate the first fragment, trityl protected imidazole carboxaldehyde 5 was treated with substituted benzylbromides and subsequent deprotection resulted in substituted imidazole carboxaldehyde 6 in moderate to IRAK inhibitor 1 good yields varied depending on substituents on alkyl bromide. likely limit widespread use.4 We have previously reported on low-cost dialkylimidazole compounds that kill amastigotes in the low nM range.5 The activity of these compounds is due to inhibition of the enzyme sterol 14-demethylase6 (CYP51), essential for the biosynthesis of ergosterol-like sterols, crucial components of the parasite membrane.7 In the acute mouse model of Chagas disease, several dialkylimidazole compounds reduced parasitemia to microscopically undetectable levels after oral administration.5, 8 However, the compounds are relatively large, hence we attempted to reduce the size of our original lead 2 while maintaining potency to arrive at inhibitors like 3 with more drug-like physicochemical properties. Open in a separate window Physique 1 Most potent Sterol-14alpha demethylase inhibitors We previously reported a very simple and straightforward synthetic route to arrive at dialkylimidazoles in good yields.5 Synthesis requires the preparation of two fragments that are then coupled under reductive amination conditions. Analogs 12a-l were obtained according to Scheme 1. To generate the first fragment, trityl guarded imidazole carboxaldehyde 5 was treated with substituted benzylbromides and subsequent deprotection resulted in substituted imidazole carboxaldehyde 6 in moderate to good yields varied depending on substituents on alkyl bromide. The second fragment 11 was derived from 7 using reported methods.5 Reductive coupling of key intermediates 11 and 6 provided the target compounds 12a-l. Open in a separate window Scheme 1 Synthesis of dialkylimidazole analogs a Preparation of analogs 12r-v is usually described in Scheme 2. Phenol derivatives 15 were reacted with alcohols in presence of DIAD and TPP in THF to generate 16 in approximately 45-50% yields. The intermediates were converted to the target compounds using the procedure described in Scheme 1. Synthesis of halogenated dialkylimidazole derivatives is usually depicted in Schemes 3 and ?and4.4. Compound 21 was synthesized as a versatile intermediate for the preparation of several analogs in this study. It was obtained inconsiderable yield from 18 by Suzuki coupling followed by bromination and further alkylation with 5. Open in a separate window Scheme 2 Preparation of dialkylimidazoles made up of 2-ethoxy-morpholines and piperidinesa Open in a separate window Scheme 3 Preparation of halogenated dialkylimidazoles a Open in a separate window Scheme 4 Synthetic technique for dialkylimidazole analogs bearing -NH2 at Ra The next fragment was easily prepared from obtainable nitro derivatives. Fragments had been coupled to create the target substances 24a-r in moderate to great yields. Likewise, all amino analogues had been prepared as referred to in Structure 4. Inside our earlier studies, inhibitors had been potent but huge and extremely hydrophobic6. Therefore we made a decision to create simplified and even more drug-like analogues with minimal molecular pounds and lipophilicity (Desk 1). We produced new constructions by changing 2 at IRAK inhibitor 1 four positions R, R1, R2 and R3 (Shape 1). All of the synthesized analogs had been examined against the medically relevant amastigote phases of IRAK inhibitor 1 IRAK inhibitor 1 amastigotes EC50(nM)placement for the terminal phenyl (R3) such as for example hydroxy and methoxy and got little influence on strength. However, the intro of an amino group in the 4-placement on R3 (12k) significantly inhibited the ethnicities at low nanomolar level with 10\collapse increase in strength (EC50=1.6 nM) weighed against substance 12. Previously explored SAR from the benzothiazole moiety 6 recommended that benzothiazole reaches the periphery from the energetic site, partially subjected to solvent. Changing it by a straightforward chloro retains the strength against and, significantly, decreases the molecular mass by 100.6 By retaining ?Cl in R2 placement, we obtained a supplementary molecular mass windowpane within Lipinski space to explore R3 with a number of heterocyclic aswell while saturated heterocyclic systems (12n-q). Nevertheless, associated modifications didn’t improve strength. In addition, replacement unit of the benzothiazole moiety at R2 with alkoxy and alkylamino connected heterocycles,.