Recent progress in chemical approaches for the development of novel neuraminidase inhibitors

Abstract

Influenza virus is the main cause of an infectious disease called influenza affecting the respiratory system including the throat, nose and lungs. Neuraminidase inhibitors are reagents used to block the enzyme called neuraminidase to prevent the influenza infection from spreading. Neuraminidase inhibitors are widely used in the treatment of influenza infection, but still there is a need to develop more potent agents for the more effective treatment of influenza. Complications of the influenza disease lead to death, and one of these complications is drug resistance; hence, there is an urgent need to develop more effective agents. This review focuses on the recent advances in chemical synthesis pathways used for the development of new neuraminidase agents along with the medicinal aspects of chemically modified molecules, including the structure-activity relationship, which provides further rational designs of more active small molecules.

Scheme 1. Hydrolysis step of sialylglycosides.

Fig. 1. DANA, zanamivir and oseltamivir phosphate structures.

Fig. 2. Structures of starting materials for the synthesis of zanamivir.

Fig. 3. Structures of starting materials for the synthesis of oseltamivir phosphate.

Fig. 4. Structure of influenza virus.

Fig. 5. Mechanism of virus entry (A) and neuraminidase inhibitors (B).

Fig. 6. Structures of 2,3-difluorosialic acid analogues.

Fig. 7. Structures of iridium(iii) complexes.

Fig. 8. Structures of chalcone derivatives.

Fig. 9. Design and synthesis of 2-thiazolylhydrazone derivatives.

Fig. 10. Structures of Neu5Ac2en-derived hPIV-3 HN inhibitors.

Fig. 11. Synthesis of acylhydrazone NA inhibitors.

Fig. 12. Structures of divalent oseltamivir analogues.

Fig. 13. Structures of aurones, chalcones, cinnamic acid analogues, pyrimidine analogues and cinnamic acid linkages.

Fig. 14. Structures of 3,4-unsaturated Neu5Ac derivatives.

Fig. 15. Structures of dUTP-ONeu5Ac and dUTP-SNeu5Ac derivatives.

Fig. 16. Structures of oseltamivir carboxylic acid (1a, OC), guanidino OC (1b, GOC) and their carboxyl bioisosteres.

Fig. 17. Structures of azo derivatives.

Fig. 18. Superimposition between the docked conformation (yellow) and the crystal structure (green) of H1N1 3TI6.

Fig. 19. Structures of cyclic peptides and the visualization of the catalytic site of influenza A (H1N1) neuraminidase.

Fig. 20. Synthesis of C5-modified DANA analogues.

Fig. 21. Synthesis of S-substituted perhalonitrobuta-1,3-diene derivatives.

Fig. 22. Structures of (TriazoleNeu5Ac2en)-A, (TriazoleNeu5Ac2en)-AdE and E-(TriazoleNeu5Ac2en)-AKE.

Fig. 23. Structures of carboxyl-modified oseltamivir analogues.

Fig. 24. Structures of bicyclo[3.1.0]hexane analogues of sialic acid.

Fig. 25. Structures of caffeic acid and epigoitrin derivatives.

Fig. 26. Structures of curcumin analogues.

Fig. 27. Structures of enzymatically synthesized 2,7-anhydro-Neu5Ac (1) and its chemoenzymatically synthesized derivatives 2–4.

Fig. 28. Structures of N-substituted oseltamivir derivatives.

Fig. 29. Structures of tested compounds.

Fig. 30. Structures of acylguanidine derivatives.

Fig. 31. Structures of reference hPIV-3 HN inhibitors (1–7) and the potential new target inhibitors (8).

Fig. 32. Synthesis of sodium baicalin.

Fig. 33. Structures of 3-amino sialosyl sulfonates and 3-guanidino sialosyl α-sulfonates.

Fig. 34. Synthesis of 1-(β-d-ribofuranosyl)-3-polyfluoroalkyl-5-phenyl-1H-pyrazoles.

Fig. 35. Structures of C-1-modified oseltamivir derivatives.

Fig. 36. Synthetic route to C9-phenyltriazole DANA analogues.

Fig. 37. Structures of isolated rupestonic acid and rupestonic acid derivatives.

Fig. 38. Structure of pterodontic acid.

Fig. 39. Neuraminidase-catalyzed hydrolysis of 20-(4-methylumbelliferyl)-α-d-N-acetylneuraminic acid (MUNANA).

Fig. 40. Structure of simpterpenoid A.

Fig. 41. Structures of isolated compounds from U. longissima.

Fig. 42. Structures of baicalin, oroxylin A-7-O-glu acid, wogonoside, baicalein, wogonin, chrysin and oroxylin A.

Fig. 43. Structures of honokiol and honokiol derivatives.

Fig. 44. Structures of isolated chromenone derivatives from Flemingia philippinensis.

Fig. 45. Structure of artocarpin.

Fig. 46. Structures of 4-dimethylaminobenzaldehyde derivatives.

Fig. 47. Structure of 3-(6-methylpyridine-3-yl)-4-[(thiophene-2-yl) methylene amino]-H-1,2,4-triazol-5(4H)-thione.

Fig. 48. Structure of kaempferol-3-0-[(4′′5′′-0-isoprotylidene)-a-l-rhamnopyranoside.

Fig. 49. Structure of 4-(arylimino)-3-alkyl-1H-1,2,4-triazol-5(4H)-thioketone derivatives.

Fig. 50. Structures of 4-(4-hydroxyphenylmethyleneamino)-1,2,4-triazol-5-thione derivatives.

Fig. 51. The synthesized N-thiazolylpyridine formamide derivatives.

Fig. 52. Structures of oxazolamide derivatives.

Fig. 53. Structures of baicalein derivatives.

Fig. 54. Structure of compound Id-5.

Fig. 55. Structures of 5-(3-phenylacryloyl)-2-benzoylaminothiazole derivatives.

Fig. 56. Structures of diterpenoids.

Fig. 57. Structures of 2-(5-nitrothiazol-2-yl)-imino-4-thiazolinone derivatives.

Fig. 58. Structures of 5-(3-phenylacryloyl)thiazole derivatives.

Fig. 59. Structures of furan formamide derivatives.

Fig. 60. Structures of (4-alkyl-5-acyl-2-thiazolyl)hydrazone derivatives.

Fig. 61. Structures of hydrazide neuraminidase inhibitors.

Fig. 62. Structures of oseltamivir derivatives.

Fig. 63. Structures of terpenoids.

Fig. 64. Structures of oseltamivir derivatives.

Fig. 65. Structures of N,N′-bis(4-methyl-7-hydroxycoumarin-8-methylene)hydrazine derivatives.

Fig. 66. Structures of 2-(2-benzylhydrazide)-5-acylthiazole derivatives.

Fig. 67. Structures of 2-(2-benzylhydrazinyl)-5-acylthiazole derivatives.

Fig. 68. Structure of tiliroside.

Fig. 69. Structures of anti-influenza derivatives.

Fig. 70. Structures of acylhydrazone derivatives.

Fig. 71. Structures of Srepolyketide B, Srepolyketide C and SEK15.

Fig. 72. Structures of thiourea derivatives.

Fig. 73. Structures of vanillin derivatives.

Fig. 74. Structures of pyridazine hydrazone derivatives.