Inhibitors of glucosamine-6-phosphate synthase as potential antimicrobials or antidiabetics – synthesis and properties

Figures & data

Scheme 1. The reaction catalysed by GlcN-6-P synthase.

Figure 1. Molecular structure of GlcN-6-P synthase. Top – Structure of E. coli GFA dimer, with GAH and ISOM active centres indicated as red and green spheres, respectively. Based on the pdbid: 1jxa matrix. Bottom – a single subunit of GlcN-6-P synthase, with a detailed presentation of active centres’ crucial residues and 5-oxo-L-norleucine covalently bound to the Cys1 residue at GAH and Glc-6-P in an open ring form at ISOM. Side chains of residues present within the radius of 4.5 Å of both ligands are drawn as thin sticks and ligands as thicker sticks. Crucial residues of superimposed C. albicans (pdbid: 2poc) and H. sapiens (pdbid: 6r4f) GlcN-6-P synthases are shown, to visualise the cross-species conservation of both the structure and conformation of the crucial amino acid residues. The observed significant variations of Cys1, Trp74 and Glu488 confirmations are due to their conformational mobility during the catalytic act.

Scheme 2. Mechanism of sugar phosphate isomerisation by GlcN-6-P synthase. Im and ImH⁺ represent the non-protonated or protonated form of the imidazole ring, respectively.

Scheme 3. (A) Antibiotics containing glutamine analogues targeting GlcN-6-P synthase. (B) Synthesis of anticapsin reported by Baldwin et al. ³⁶

Scheme 4. (A) Synthesis of GlcN-6-P synthase inhibitors containing l-2,3-diaminopropanoic moiety. (B) Molecular mechanism of GlcN-6-P synthase inactivation at GAH by FMDP⁴³.

Scheme 5. Synthesis of GlcN-6-P synthase inhibitors containing l-2,3-diaminopropanoic moiety.

Scheme 6. Synthesis of antimicrobials incorporating FMDP.

Scheme 7. Synthesis of the mechanism-based GlcN-6-P synthase inhibitor, according to Massiere et al.⁵⁸

Scheme 8. Synthesis of electrophilic glutamine-based inhibitors of GlcN-6-P synthase.

Scheme 9. Syntheses of GlcN-6-P and Fru-6-P analogues targeting GlcN-6-P synthase.

Scheme 10. Synthesis of fructosimine-6-P analogues.

Scheme 11. (A–C) Synthesis of transition state cis-enolamine analogues. (D) ADGP binding at E. coli GlcN-6-P synthase ISOM active site (based on pdbid: 1mos); H-bonds are shown by dashed lines.

Scheme 12. (A) Syntheses of putative GlcN-6-P synthase inhibitors, according to Vijesh et al.⁷⁰ (B) Syntheses of presumable GlcN-6-P synthase inhibitors, according to Tomi et al.⁷²

Scheme 13. (A) Synthesis of disubstituted 1,2-oxazole and 1,2-diazole based possible inhibitors of GlcN-6-P synthase, according to Ismail et al.⁷³ (B) Predicted binding mode of compound 55 at the ISOM active site; H-bonds are shown by dashed lines.

Scheme 14. Synthesis of 1,3-oxazole- and 1,2-diazole-based putative inhibitors of GlcN-6-P synthase, according to Katariya et al.⁷⁴

Scheme 15. (A) Synthesis of a potential GlcN-6-P synthase inhibitor, according to Bahare et al.⁷⁵ (B) Synthesis of GlcN-6-P synthase inhibitor, according to Omar et al.⁷⁶ (C) Predicted binding mode of 67c at the ISOM active site; H-bonds are shown by dashed lines; hydrophobic interactions are shown by wavy lines.

Scheme 16. Synthesis of triazole-based putative inhibitors of GlcN-6-P synthase, according to Rajasekaran et al.⁷⁷

Scheme 17. Synthesis of trisubstituted 1,2,3-triazole as a potential inhibitor of GlcN-6-P synthase, according to Aouad et al.⁷⁸

Scheme 18. Synthesis of 1,3,4-oxadiazoles derivative as a potential inhibitor of GlcN-6-P synthase, according to Shyma et al. ⁷⁹

Scheme 19. Synthesis of 2,5-disubstituted oxadiazole derivative as a potential inhibitor of GlcN-6-P synthase, according to Sindhe et al.⁸²

Scheme 20. Synthesis of 2,4,6-trisubstituted pyridine-based putative inhibitors of GlcN-6-P synthase, according to Kenchappa et al.⁸⁴

Scheme 21. Synthesis of trisubstituted pyrimidine-based putative inhibitors of GlcN-6-P synthase, according to Venkatesh et al.⁸⁶

Scheme 22. Synthesis of 2,4,6-trisubstituted 1,3-diazine-based potential inhibitors of GlcN-6-P synthase, according to Bakr et al.⁸⁷

Scheme 23. Synthesis of barbiturate- and thiobarbiturate-based possible GlcN-6-P synthase inhibitors, according to Kenchappa et al.^88,90

Scheme 24. (A) Synthesis of benzofuran-2-yl derivative-based potential inhibitor of GlcN-6-P synthase, according to Aswathanarayanappa et al.⁹¹ (B) Synthesis of β-amino carbonyl derivatives of benzofuran as potential GlcN-6-P synthase inhibitors, according to Kenchappa et al.⁹²

Scheme 25. Synthesis of benzodiazepine-based potential inhibitors of GlcN-6-P synthase, according to Kenchappa et al.⁹³

Scheme 26. Synthesis of imidazo[4,5-C]pyridine-based potential GlcN-6-P synthase inhibitor, according to Jose et al.⁹⁴ and its predicted binding mode to the GAH active centre of GlcN-6-P synthase; H-bonds are shown by dashed lines.

Scheme 27. (A) Synthesis of curcumin derivatives as potential inhibitors of GlcN-6-P synthase, according to Kumar et al.⁹⁵ (B) Predicted binding mode of compound 117 to the GAH domain of GlcN-6-P synthase; H-bonds are shown by dashed lines.

Scheme 28. (A) Synthesis of fluorine-substituted pyrazolopyrimidine-based putative inhibitor of GlcN-6-P synthase, according to Khan et al.⁹⁷ (B) Presumable binding mode of 119 to GlcN-6-P synthase at the ISOM active site; H-bonds are shown by dashed lines.

Scheme 29. Synthesis of 5,7-dichloro-1,3-benzoxazole-2-thiol derivatives as potential inhibitors of GlcN-6-P synthase, according to Satyendra et al. (path A)^98,99. Synthesis of 5,7-dichloro-1,3-benzoxazole-2-yl derivatives as potential inhibitors of GlcN-6-P synthase according to Jayanna et al. (path B)¹⁰⁰.

Scheme 30. Synthesis of a potential GlcN-6-P synthase inhibitor, according to Venkatesh et al.^101,102 and its predicted binding mode to the GAH domain; H-bonds are shown by dashed lines.

Scheme 31. Synthesis of quinazolinone-based putative inhibitors of GlcN-6-P synthase, according to Kumara et al.¹⁰³

Scheme 32. (A) Syntheses of coumarin based potential inhibitors of GlcN-6-P synthase, according to Kenchappa (path A)⁹², Kumar (path B)¹⁰⁷ and Helmy et al. (path C)¹⁰⁸. (B) Synthesis of 4-chromone-based inhibitor of GlcN-6-P synthase, according to Devi et al.¹⁰⁹

Scheme 33. Synthesis of potential GlcN-6-P synthase inhibitors, according to Elkanzi et al.¹¹⁰

Scheme 34. Syntheses of: (A) uranyl(VI) complex; (B) vanadium(V) complex; (C) cobalt(II) complex with antimicrobial activity, according to Ebrahimipour et al.^113–115

Scheme 35. Synthesis of metal complexes, potential GlcN-6-P synthase inhibitors, according to (A) Onwudiwe et al.¹¹⁶ and (B) Wang et al.¹¹⁸

Scheme 36. Structure of aaptamine and synthesis of RO0509347 developed at Hoffman La-Roche Inc.¹²²

Figure 2. The hypothetical complex of RO0509347 with human GlcN-6-P synthase. Drawing based on the results of docking calculations to the hGFAT2 matrix (pdbid: 6r4f)¹²³, performed with the use of Autodock 4.2, according to the procedure described previously¹²⁴. A single subunit of the tetrameric enzyme is shown, with GAH and ISOM active centres indicated as red and green spheres respectively. A flexible linker joining both domains of the enzyme is coloured blue.

Scheme 37. (A) Synthesis of 1,2-diazole-based inhibitors of GlcN-6-P synthase according to Khan et al.¹²⁵ (B) Synthesis of trisubstituted 1,2-diazole-based inhibitors of GlcN-6-P synthase according to Ebenezer et al.¹²⁶

Scheme 38. (A) Syntheses of a possible GlcN-6-P inhibitor, according to Sarojini et al.^127,128 and its predicted binding mode to GlcN-6-P synthase; H-bonds are shown by dashed lines.

Scheme 39. Synthesis of trisubstituted 1,2,4-triazole as a potential inhibitor of GlcN-6-P synthase, according to Krishna et al.¹²⁹

Scheme 40. Synthesis of the 1,3,4-thiadiazole derivative as a putative inhibitor of GlcN-6-P synthase, according to Siwek et al.¹³⁰

Scheme 41. Synthesis of spiro pyrrolidine-based putative inhibitor of GlcN-6-P synthase, according to Askri et al.¹³²

Scheme 42. (A) Synthesis of fluorinated pyridazinone derivatives as a potential inhibitor of GlcN-6-P synthase, according to Sowmya et al.¹³³ (B) Synthesis of pyridazinone derivatives as a putative inhibitor of GlcN-6-P synthase, according to Nagle et al.¹³⁴

Scheme 43. Synthesis of 2-chloroquinolin-3-yl ester derivatives as potential GlcN-6-P inhibitors, according to Tabassum et al. (path A)¹³⁹. Synthesis of quinoline-based epoxides, according to Preveena et al. (path B)¹³⁸.

Scheme 44. Synthesis of isoquinoline derivatives as potential inhibitors of GlcN-6-P synthase, according to Borse et al.¹⁴⁰

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