Recent Progress in Synthesis, POM Analyses and SAR of Coumarin-Hybrids as Potential Anti-HIV Agents-A Mini Review

Abstract

The human immunodeficiency virus (HIV) is the primary cause of acquired immune deficiency syndrome (AIDS), one of the deadliest pandemic diseases. Various mechanisms and procedures have been pursued to synthesise several anti-HIV agents, but due to the severe side effects and multidrug resistance spawning from the treatment of HIV/AIDS using highly active retroviral therapy (HAART), it has become imperative to design and synthesise novel anti-HIV agents. Literature has shown that natural sources, particularly the plant kingdom, can release important metabolites that have several biological, mechanistic and structural representations similar to chemically synthesised compounds. Certainly, compounds from natural and ethnomedicinal sources have proven to be effective in the management of HIV/AIDS with low toxicity, fewer side effects and affordability. From plants, fungi and bacteria, coumarin can be obtained, which is a secondary metabolite and is well known for its actions in different stages of the HIV replication cycle: protease, integrase and reverse transcriptase (RT) inhibition, cell membrane fusion and viral host attachment. These, among other reasons, are why coumarin moieties will be the basis of a good building block for the development of potent anti-HIV agents. This review aims to outline the synthetic pathways, structure-activity relationship (SAR) and POM analyses of coumarin hybrids with anti-HIV activity, detailing articles published between 2000 and 2023.

Keywords: AIDS; HAART; HIV; POM; coumarin; reverse transcriptase; synthesis.

Figure 11

The Concept and Applications of POM Theory in the identification and optimisation of pharmacophore sites of various classes of drugs developed by Prof. T. Ben Hadda (the principal inventor of POM Theory) in collaboration with the NCI and TAACF of the USA [76,77].

Figure 1

Structure of different coumarins.

Scheme 1

Synthetic pathways for the synthesis of hydroxymethyl DCK analogues. Conditions and reagents: (i) N-bromosuccinimide in benzene, reflux; (ii) NaOAc, acetic anhydride, reflux; (iii) reflux, HCl (2N) in EtOH; (iv) diethylamine in toluene, reflux; (v) hexanemethylenetetramine in CHCl₃, reflux; (vi) EtOH, HCl (2N), 100 °C.

Figure 2

SAR representation of hydroxymethyl DCK analogues.

Scheme 2

Synthetic route for the synthesis of 1,2,4-triazolylcoumarin hybrid. Reagents and conditions: (i) ClCH₂CN; (ii) CH₂Cl₂, SbCl₅, −60 °C; (iii) −60 °C to 23 °C, CH₂Cl₂; (iv) NH₃, NaHCO₃, MeCN, 2 h, 0 °C. 11a–16a R₁ = R₂ = CH₃; b R₁ = R₂ = Et; c R₁ = R₂ = Et; d R₁ = CH₃, R₂ = i-Pr, e R₁ = R₂ = (CH₂)₅.

Scheme 3

Synthetic pathway for the synthesis of novel hybrid 17. Reagents and conditions: (i) NH₃, NaHCO₃, MeCN, 2 h, 0 °C.

Figure 3

SAR representation of 1H-1,2,4-triazolycoumarin hybrids.

Scheme 4

A synthesis pathway for the synthesis of 23a–i and 24a–i. Reaction and condition; (i) POCl₃, anhydrous ZnCl₂, 70 °C; (ii) POCl₃, glacial acetic acid; (iii) piperidine, CHCl₃, 80 °C.

Figure 4

SAR presentation of new coumarinyl chalcone analogues 23a–i and 24a–i.

Scheme 5

A synthetic pathway for the synthesis of PETT analogues.

Figure 5

SAR representation of PETT analogues.

Scheme 6

Synthetic pathway for the synthesis of hybrid 40a–h. Reagents and conditions: (i) THF, DCC, TEA, 24 h, 20–25 °C, N₂; (ii) EtOAc, H₂, 5% Pd/C, 20–25 °C, 48 h; (iii) THF, DCC, TEA, 20–25 °C, 24 h, N₂.

Figure 6

SAR representation of hybrids 40a–h.

Scheme 7

A synthetic pathway for the synthesis of 45, 46, 48 and 49.

Scheme 8

Synthesis of compound 57. Reagents: (i) chloroacetyl chloride; (ii) K₂CO₃, potassium phthalimide; (iii) hydrazine hydrate.

Scheme 9

Synthesis of compounds 59 and 60.

Scheme 10

Synthetic pathway for hybrids 67a–m and 68a–m. Reagents and conditions: (i) 10% NaHCO₃/acetone (ii) acetone/10% NaHCO₃ (iii) 10% NaHCO₃/dioxane.

Scheme 11

Synthesis of compounds 71a–m and 72a–m. Reagents and conditions: (i) 10% NaHCO₃/acetone (ii) acetone/10% NaHCO₃ (iii) 10% NaHCO₃/dioxane.

Scheme 12

Synthesis of AZT-coumarin derivatives 80a–e. Reagents and conditions (i) CHCl₃, DABCO, rt; (ii) AcOH, HCl, reflux; (iii) THF, propargylamine; (iv) Cu₂SO₄.5H₂O, C₆H₇NaO₆ (sodium ascorbate), H₂O-THF.

Figure 7

SAR representation of hybrids 80a–e.

Scheme 13

Synthetic pathways for the synthesis of coumarin–AZT hybrids 85a–e. Reagents and condition: (i) CHCl₃, DABCO, rt; (ii) AcOH, HCl, reflux.

Figure 8

SAR representation of hybrids 85a–e.

Scheme 14

Synthetic pathways for the synthesis of diazocoumarin derivatives. Reagents and condition: (i) H₂SO₄, ethanol, reflux, 24 h (ii) NH₂-NH₂.OH, ethanol (6 eq.), reflux, 96 h (iii) CS₂, ethanol, KOH, reflux, 4h (iv) 10% aq. NaOH, methanol, substituted aryl/alkyl halides, r.t (v) 10% sodium nitrite, 6 M HCl, 0–5 °C (vi) 10% aq. Na₂CO₃, stir, 0–5 °C.

Figure 9

SAR representation of hybrids 93a–h.

Scheme 15

Synthetic pathways for synthesis of coumarin-3-carbohydrazide derivatives. Reagents and conditions: (i) piperidine, diethyl malonate, ethanol, CH₃COOH, 80 °C, 12 h (ii) ethanol, NaOH, reflux (iii) oxalyl chloride, reflux, 8 h. (iv) CH₃OH, Conc. H₂SO₄, reflux, 24 h (v) 65% N₂H₄.H₂O, 80–90 °C, overnight. (vi) Na₂CO₃, room temperature, overnight.

Figure 10

SAR representation of hybrids 98a–t.

Scheme 16

Synthetic pathways for the synthesis of hybrids 116 and 117. Reagents and conditions: (i) POCl₃, ZnCl₂; (ii) POCl₃, ZnCl₂ (iii) gla CH₃COOH, POCl₃ (iv) ethylacetate, Na; (v) Ethanol, HCl (vi) 3,4-DABP (vii) POCl₃, 1,2-dichloromethane, Pd-C/H₂ (viii) Ph-NHNH₂.

Scheme 17

Molecular structure of compounds 126a–128i. (a) A synthetic pathway for the synthesis of amine derivatives. Reagents and conditions: (i) CH₃CN, i-BuNH₂, 80 °C, 6 h; (ii) DIEA, aryl sulfonyl chloride, DMAP(Cat.), THF, 0 °C~r.t, 3–5 h; (iii) CH₂Cl₂-CF₃COOH (1:1), 0 °C~r.t, 3 h; (iv) 50 psi, H₂ (gas), 10% Pd/C, CH₃OH, r.t, 2 h. (b) Synthetic pathways for the synthesis of coumarin–amide hybrids 126a–128i. Reagents and conditions: (i) HOBt, EDCI, anhydrous DMF, DMAP, Argon, 0 °C~r.t, 3 h. (c) Synthetic pathways for the synthesis of coumarin–carbide hybrids 126j–128k. Reagents and condition: (i) Anhydrous DCM, DIEA, anhydrous THF, 0 °C~r.t, 1.5 h. (d) Synthetic pathways for the synthesis of coumarin–amine hybrids 123–125l. Reagents and conditions: (i) anhydrous EtOH, DIEA, reflux, 7 h.

Scheme 17

Molecular structure of compounds 126a–128i. (a) A synthetic pathway for the synthesis of amine derivatives. Reagents and conditions: (i) CH₃CN, i-BuNH₂, 80 °C, 6 h; (ii) DIEA, aryl sulfonyl chloride, DMAP(Cat.), THF, 0 °C~r.t, 3–5 h; (iii) CH₂Cl₂-CF₃COOH (1:1), 0 °C~r.t, 3 h; (iv) 50 psi, H₂ (gas), 10% Pd/C, CH₃OH, r.t, 2 h. (b) Synthetic pathways for the synthesis of coumarin–amide hybrids 126a–128i. Reagents and conditions: (i) HOBt, EDCI, anhydrous DMF, DMAP, Argon, 0 °C~r.t, 3 h. (c) Synthetic pathways for the synthesis of coumarin–carbide hybrids 126j–128k. Reagents and condition: (i) Anhydrous DCM, DIEA, anhydrous THF, 0 °C~r.t, 1.5 h. (d) Synthetic pathways for the synthesis of coumarin–amine hybrids 123–125l. Reagents and conditions: (i) anhydrous EtOH, DIEA, reflux, 7 h.

Scheme 18

Synthesis of novel chromeno–-chromenone hybrids. Reagents and conditions: (i) EtOH, L-proline, reflux, 12–14 h, 78–90%.

Figure 12

Opening/closing ring of coumarin moiety [75].

Figure 13

Identification of antiviral pharmacophore sites of coumarin-hybrid compounds.