A review on synthetic account of 1,2,4-oxadiazoles as anti-infective agents

Abstract

Most of the currently marketed drugs consist of heterocyclic scaffolds containing nitrogen and or oxygen as heteroatoms in their structures. Several research groups have synthesized diversely substituted 1,2,4-oxadiazoles as anti-infective agents having anti-bacterial, anti-viral, anti-leishmanial, etc. activities. For the first time, the present review article will provide the coverage of synthetic account of 1,2,4-oxadiazoles as anti-infective agents along with their potential for SAR, activity potential, promising target for mode of action. The efforts have been made to provide the chemical intuitions to the reader to design new chemical entity with potential of anti-infective activity. This review will mark the impact as the valuable, comprehensive and pioneered work along with the library of synthetic strategies for the organic and medicinal chemists for further refinement of 1,2,4-oxadiazole as anti-infective agents.

Keywords: 1,2,4-Oxadiazoles; Anti-bacterial; Anti-infective; Anti-malarial; Synthesis.

Fig. 1

Exponential growth of on-going research on 1,2,4-oxadiazoles retrieved by Scopus on Sept 27, 2021 using the keywords “1,2,4-oxadiazoles.” [24]

Fig. 2

Chemical structures of commercial drugs and natural products based on a 1,2,4-oxadiazole scaffold

Fig. 3

Scaffolds of the 1,2,4-oxadiazoles with different anti-infective activities [–52]

Fig. 4

Synthetic strategies for accessing anti-infective 1,2,4-oxadiazole scaffold

Scheme 1

Synthesis of 1,2,4-oxadiazoles (7/8) having anti-bacterial and anti-fungal activity. Conditions: (i) Chloramine-T, EtOH, reflux, 3 h; (ii) Na₂CO₃, aq. EtOH, reflux, 5–6 h; (iii) EDC^.HCl, DCM, 0–30 °C, 1–2 h, then rt for 6 h followed by 110 °C, 6 h; (iv) Br₂, DCM, reflux, 1 h

Scheme 2

Synthetic strategy for 3-aryl-5-propyl-1,2,4,oxadiazoles (12) reported by Srivastava and co-workers. Conditions: (i) EtOH, H₂O, rt, 5–8 days; (ii) MnO₂, (3.8 equiv), DCM, rt, 2 h

Scheme 3

Synthesis of 3-(4-susbstituted-aryl)-1,2,4-oxadiazolyl-N-acylhydrozone (18) acting against T. cruzi. Conditions: (i) THF, reflux, 4.5 h; (ii) EtOH, 0 °C, 60 min; (iii) H₂SO₄, EtOH, rt,10 min

Scheme 4

Synthetic strategy of 3,5-disubstituted oxadiazoles (16 and 22) as trypanosomicidal and anti-malarial agents. Conditions: (i) Na₂CO₃, H₂O/MeOH, 4 h, reflux; (ii) dry THF, reflux, 4–4.5 h; (iii) EtOH, 0 °C, 2 h; (iv) H₂SO₄ or CeCl₃^.7H₂O (10 mol%), EtOH, 40 °C,10–30 min

Scheme 5

Synthesis strategy of (E)-3 alkyl-5-styryl-1,2,4-oxadiazoles (27) as anti-tubercular agents adopted by Upare et al. Conditions: (i) piperidine, pyridine, 110 °C,10–12 h; (ii) CDI, PhMe, rt, 3–4 h followed by 100–110 °C, 5–6 h

Scheme 6

Strategy for the multi-step synthesis of phenyl oxadiazole compound (36) acting against human rhinovirus. Conditions: (i) SOCl₂, DMF, 70 °C; (ii) NH₃, H₂O, THF, 0–25 °C, 5 h; (iii) TFAA, pyridine, 16 h; (iv) EtOH, 90 °C,16 h; (v) TFAA, pyridine, 0–120 °C, 16 h; (vi) neat, 150 °C, 90 h

Scheme 7

Synthesis of nitrofuryl substituted 3-amino-1,2,4-oxadiazoles (39/40) and 5-amino-1,2,4-oxadiazoles (42/43) having potent anti-microbial activity. Conditions: (i) HNO₃, Ac₂O, 15 °C, 30 min; (ii) 10% HCl (ethanolic), 3 h

Scheme 8

Synthesis of 1,2,4-oxadiazoles (49/51/53) as non-β-lactam inhibitors. Conditions: (i) Cul, Cs₂CO₃, N,N-dimethyl, glycine HCl, 1,4-dioxane, 90 °C; (ii) NH₂OH, EtOH, reflux, 3 h; (iii) DIPEA, DCM, 0 °C—> rt; (iv) TBAF, THF, rt, 24 h; (v) 4-TBDMS-BzCl, PhMe, 120 °C, overnight; (vi) TBAF, (1 equiv), THF, < 1 min; (vii) 4-NO₂-BzCl, PhMe, reflux, 5.5 h; (viii) Fe, H₂O, HCl, EtOH, 95 °C, 2 h

Scheme 9

Structure activity relationship of 1,2,4-oxadiazole antibiotics 58. Conditions: (i) K₂CO₃, DMF, 60–100 °C or Cul, Cs₂CO₃, N,N-dimethylglycine^.HCl 1,4-dioxane, 90 °C; (ii) NH₂OH, EtOH and (iii) pyridine/toluene/1,4-dioxane

Scheme 10

Synthesis of 1,2,4-oxadiazole derivatives (62) having anti-microbial property. Conditions: (i) EtOH, H₂O, reflux, 5 h and (ii) PhMe, reflux, 5 h

Scheme 11

Synthesis of 3′,4′-diaryl-4′H-spiro[indoline-3,5′-[1′,2′,4′]oxadiazol]-2-ones (66) via DMAP-catalyzed domino reaction. Conditions: (i) EtOH, rt, 3 h, DMAP (10 mol%), rt, 3 h

Scheme 12

Synthesis of 1,2,4-oxadiazoles (73) from N-aryl amidoxime (72) and alkyl ester (71). Conditions: (i) NaHCO₃, EtOH, 80 °C, 6 h, (ii) NaOH, DMSO, rt; (iii) NaOH, DMSO, rt, 4 h

Scheme 13

Synthesis of 2-morpholinoquinoline integrated 1,2,4-oxadiazole scaffolds (81). Conditions: (i) I₂, THF, rt, 30 min; (ii) DMF, K₂CO₃, reflux, 2 h; (iii) NH₂OH^.HCl, Na₂CO₃, EtOH, reflux, 5 h and (iv) EDC^.HCl, DCM, rt, 30 min then reflux, 2 h; (v) NaOAc, EtOH, reflux, 3 h

Scheme 14

Synthetic scheme for 3,5-disusbtituted 1,2,4-oxadiazoles (89) as anti-fungal agents. Conditions: (i) MeOH, reflux, 8 h; (ii) CuCN, L-proline, DMF, 11 h; (iii) EtOH, rt; (iv) PhMe; (v) NaOH, THF, 2 h; (vi) 0 °C, 8 h

Scheme 15

Synthesis of 1,2,4-oxadiazoles (93) active as anti-bacterial agents. Conditions: (i) Br₂, Et₃N, CHCl₃, MeOH, rt, 10 min