A recent update on new synthetic chiral compounds with antileishmanial activity

Abstract

Parasitic diseases, including malaria, leishmaniasis, and trypanosomiasis, affect billions of people and are responsible for almost 500,000 deaths/year. In particular, leishmaniasis, a neglected tropical disease, is considered a global public health problem because current drugs have several drawbacks including to toxicity, high cost, and drug resistance, which result in a lack of effective and readily available therapies. Therefore, the synthesis of new, safe, and effective molecules still requires the attention of the scientific community. Moreover, it is well known that chirality plays a crucial role in the antiparasitic activity of molecules, driving the design of their synthesis. Therefore, in this review we report a recent update on new chiral compounds with promising antileishmanial activity, focusing on synthetic approaches. Where reported, in most cases the enantiopure compound has shown better potency against the protozoa than its enantiomer or corresponding racemic mixture.

Keywords: chiral catalysis; chiral pool; chiral resolution; imidazoxazines; imidazoxazoles; kinetic resolution; leishmania; medicinal chemistry; natural products; peptides.

FIGURE 1

Main commercial drugs against Leishmaniasis

SCHEME 1

Reagents and conditions: (i) acetyl chloride, anhydrous AlCl₃, 1,2‐dichloroethane, 0°C to rt, 24 h, under Ar; (ii) m‐CPBA, TFA, CH₂Cl₂, 0°C to rt, 22 h; (iii) CrO₃, AcOH, 0°C to rt, 20 h; (iv) K₂CO₃, MeOH, rt, 3.5 h; (v) LiI, 2,4,6‐collidine, reflux, 3 h, under argon, then H₂O (0°C) and 6 N HCl (to pH = 1)

SCHEME 2

Reagents and conditions: (i) MsCl, Et₃N, dry CH₂Cl₂, 0°C to rt, 3 h; (ii) 6‐([triisopropylsilyl]oxy)hexan‐1‐ol, NaH (60% in mineral oil), dry THF, reflux, overnight; (iii) m‐CPBA, CH₂Cl₂, 0°C to rt, overnight; (iv) (S,S)‐Co‐salen catalyst, AcOH, THF, H₂O, 0°C to rt, 16 h; (v) 3‐butenylmagnesium bromide, CuI, dry THF, −78°C to rt, 2 h; (vi) m‐CPBA, CH₂Cl₂, 0°C to rt, 2 h, then (±)‐CSA, 0°C to rt, 5 h (syn alcohol by flash column chromatography); (vii) (PhO)₂P(O)N₃, DIAD, PPh₃, Et₃N, 0°C to rt, overnight; (viii) 11, CuSO₄·5H₂O, sodium ascorbate, t‐BuOH:H₂O = 1:1, rt, 16 h; (ix) (±)‐CSA, CH₂Cl₂,MeOH, rt; (x) NaN₃, DMF, 40°C, overnight; (xi) PPh₃, THF, rt, overnight then H₂O; (xii) 14, EDC hydrochloride, DMAP, CH₂Cl₂, rt, overnight

SCHEME 3

Reagents and conditions: (i) BF₃·Et₂O, Et₂O, 0°C to r.t, 24–48 h; (ii) Br₂, acetone, H₂O, rt, 3 h; (iii) Et₃N, CH₂Cl₂, rt, 3 h; (iv) NaBH₄, dry MeOH, 0°C to rt, 2 h; (v) acyl chloride [i.e., 4‐nitrobenzoyl chloride, 4‐fluorobenzoyl chloride, (1,1′‐biphenyl)‐4‐carbonyl chloride, 4‐methylthiophene‐2‐carbonyl chloride], Et₃N, CH₂Cl₂ dry, 0°C, 1 h, then rt, 18 h

SCHEME 4

Reagents and conditions: (A) (i) R‐CHO, AcOH, rt, 30 min, then KCN, rt, TLC monitored; (ii) H₂O₂ (30% v/v), K₂CO₃, MeOH:DMSO = 10:1, rt, 5–24 h; (iii) NaBH₄, BF₃·EtO₂, dry THF, −5°C, 1 h, then rt, overnight; (iv) 1. CS₂, Et₃N, EtOH, rt, TLC monitored; 2. Boc₂O, DMAP, EtOH, −5°C, 5 min, then rt, 2 h. (B) (i) NH₄Cl, TBTU, Et₃N, CH₃CN, rt, 1–3 h. (ii) NaBH₄, BF₃·EtO₂, dry THF, −5°C, 1 h, then rt, overnight; (iii) 1. CS₂, Et₃N, EtOH, rt, TLC monitored; 2. Boc₂O, DMAP, EtOH, −5°C, 5 min, then rt, 2 h

SCHEME 5

Reagents and conditions: (i) 32, EDC hydrochloride, HOBt, NMM, DMF, 0°C to rt, 4 h; (ii) 1. Tf₂O, 2‐chloropyridine, DCM, −78°C to 0°C, 15 min. 2. RuCl[(R,R)‐TsDPEN](p‐cymene), Et₃N/HCO₂H (2:5), 0°C to rt, 10 h; (iii) (a) Boc₂O, (i‐Pr₂)EtN, DMAP, CH₂Cl₂, rt, 2 h (34a to 35a) or (b) MeOCOCl, (i‐Pr₂)EtN, DMAP, CH₂Cl₂, rt, 10 h (34b to 35b); (iv) Pd (OAc)₂, (t‐Bu)₂PMeHBF₄, K₂CO₃, DMA, 130°C; (v) (c) ZnBr₂, CH₂Cl₂, rt, 8 h (36a to 37a) or (d) LiAlH₄, THF, 0°C to rt, 20 h (36b to 37b)

SCHEME 6

Reagents and conditions: (i) PhSO₂Cl, (i‐Pr)₂EtN, CH₃CN, 80°C, 5 h, then Zn, AcOH, CH₂Cl₂, 0°C to rt, 2 h; (ii) NCS, DMF, 0°C, 1 h, then rt, 1 h; (iii) NaNO₂, aq. HCl, H₂O, 0°C, 2 h, then KI, H₂O, 0°C, 2 h; (iv) 40, Pd (OAc)₂/SPhos, K₂CO₃, THF, H₂O, 75°C, 6 h; (v) N‐iodosuccinimide, p‐TsOH, CH₂Cl₂, 40°C, 6 h; (vi) 42, Pd‐PEPPSI‐IPr, Cs₂CO₃, 4 Å molecular sieves, dioxane, 90°C, 14 h; (vii) I₂, KOH, DMF, rt, 6 h; (viii) neat, 150°C, 3 h, under Ar, then [Pd (allyl)Cl]₂/44, Ag₂CO₃, Cs₂CO₃, toluene, 70°C, 12 h; (xi) Bu₄NOH, THF, 80°C, 8 h

SCHEME 7

Reagents and conditions: (i) 48, CH₃CN, TBTU, Et₃N, rt, 5 h; (ii) 50, CH₂Cl₂/aq. Na₂CO₃, rt, 3 h; (iii) CH₂Cl₂ dry, Ph₃P, I₂, (i‐Pr₂)EtN, rt, overnight; (iv) piperidine in CH₂CH₂, rt, 12 min, then CH₃CN, DMAP, reflux 19 h

SCHEME 8

Reagents and conditions: (i) NaCN, α‐amino acid alkyl ester hydrochloride, DMSO/H₂O 29:1 (v/v), rt, 48 h; (ii) 1. H₂SO₄ 97%, CH₂Cl₂, rt, 24 to 48 h. 2. ice and then aq. NH₃ 26% to pH 7–8; (iii) 1. (Me₃Si)₂NK, THF, 0–5°C, then rt, 1 h, under Ar. 2. benzyl 2‐bromoacetate, DMF, rt, 48 h, under Ar; (iv) H₂/Pd‐C 10%, EtOH‐EtOAc 3:2 (v/v), 50 psi, rt, 3 h; (v) 1. CDI, THF, 28°C, 1 h, under Ar. 2. O‐benzylhydroxylamine hydrochloride, Et₃N, 28°C, 25 h, under Ar; (vi) H₂/Pd‐C 10%, EtOH, 50 psi, rt, 3 h

SCHEME 9

Reagents and conditions: (A) (reaction time monitored by TLC) (i) 61, (NH₂)₂CO, SnCl₂·2H₂O. CH₃CN, reflux; (ii) SOCl₂, DMF (1 drop), CH₂Cl₂, reflux; (iii) 63, NMM, DMF, reflux. (B) (i) 65, SOCl₂, DMF (1 drop), CH₂Cl₂, reflux, 18 h, under N₂; (ii) L‐amino acid methyl esters 66a‐d, Et₃N, DCM, 4 h; (iii) TFA:H₂O = 1:1, CH₂Cl₂, 0°C, 2 h; (iv) 68a, CH₂Cl₂, reflux, 16 h; (v) 1‐M NaOH, MeOH, rt, overnight; (vi) 1‐M HCl (to pH 2–3). (C) (i) L‐amino acid methyl esters 66a‐d, CH₂Cl₂, reflux, 16 h; (ii) 1‐M NaOH, MeOH, rt, overnight then 1‐M HCl (to pH 2)

SCHEME 10

Reagents and conditions: (i) NH₄SCN, Ac₂O, 100°C, 30 min

SCHEME 11

Reagents and conditions: (i) phthalic anhydride, 215°C, 2 h, then AcOH, reflux, 30 min; (ii) Fe powder, AcOH, H₂O, acetone, reflux, 8 h; (iii) NaNO₂, AcOH:H₂O = 1:1, 0°C, 3 h, then NaN₃, 0°C, 30 min; (iv) NH₂NH₂·H₂O, MeOH, rt, 1 h, then 1‐M NaOH, rt; (v) sodium ascorbate, CuSO₄, propiolic acid, EtOH:H₂O = 1:1, rt, 12 h; (vi) 66a or 66b, DCC, HOBt, dry CH₂Cl₂, rt, 48 h

SCHEME 12

Reagents and conditions: (i) 79, piperidine, DMF:H₂O = 20:3, 120°C, 6 h; (ii) H₂N‐L‐Leu‐Aib‐OMe 81, DCC, HOBt, Et₃N, CH₂Cl₂ dry, 0°C to rt, 48 h

SCHEME 13

Reagents and conditions: (i) TFA, CH₂Cl₂, 0°C to rt, 30 min; (ii) 85, HOBt, EDC hydrochloride, CH₂Cl₂, 0°C, 10 min, then DIPEA, rt, 12 h; (iii) LiOH·H₂O, THF:MeOH:H₂O = 3:1:1, 0°C to rt, 1 h; (iv) EtOCOCl, Et₃N, aq. NH₃, THF, −20°C to 0°C, 1.5 h; (v) Ag₂O, MeI, DMF, 0°C to rt, 12 h

SCHEME 14

Schematic representation for the synthesis of all‐hydrocarbon stapled α‐helical peptides 90 and 91

SCHEME 15

Reagents and conditions: (i) (‐)‐diisopropyl‐D‐tartrate, Ti (Oi‐Pr)₄, CH₂Cl₂ dry, −30°C, 1 h, under N₂, then anhydrous TBHP, dry CH₂Cl₂, −30°C, 1 h then −5°C, 1 h, under N₂; (ii) 94, K₂CO₃, MeOH, 60°C, 22 h; (iii) p‐nitrobenzenesulfonyl chloride, Et₃N, CH₂Cl₂, 0°C to 30°C, 3 h; (iv) 12.5‐M NaOH, CH₂Cl₂ 15°C, 1 h; (v) 97, (i‐Pr)₂EtN, 115°C, 2 h; (vi) K₂CO₃, DMF, 60°C, 6 h

FIGURE 2

Most promising 2‐nitroimidazoxazine derivatives

SCHEME 16

Reagents and conditions: (A) (i) preparative chiral HPLC (Chiral Pak IA: Amylose derivatives tris(3,5‐dimethylphenylcarbamate); (ii) K₂CO₃, aq MeOH, 20°C, 4 h; (iii) 1‐bromo‐4‐(bromomethyl)benzene, NaH, DMF, 0°C to rt, 7 h; (iv) [4‐(trifluoromethoxy)phenyl] boronic acid, toluene, EtOH, 2‐M Na₂CO₃, Pd (dppf)Cl₂, 90°C, 1 h, under N₂. (B) (i) 112, K₂CO₃, DMF, 70°C, 19–72 h; (ii) 1‐M HCl, MeOH, 0°C, 6 h; (iii) TsCl, pyridine, −10°C to rt, 14 h; (iv) DBU, CH₂Cl₂, 0°C, 9 h; (v) 6‐bromopyridin‐3‐ol, K₂CO₃, methyl ethyl ketone, 80°C, 19–42 h; (vi) NaH, DMF, 0°C, 3 h; (vii) (4‐fluorophenyl) boronic acid or [4‐(trifluoromethoxy)phenyl] boronic acid, DMF, (toluene, EtOH), 2‐M Na₂CO₃, Pd (dppf)Cl₂, 80°C, 4 h, under N₂. The (S)‐enantiomer can be obtained starting from (S)‐4‐(2‐iodoethyl)‐2,2‐dimethyl‐1,3‐dioxolane. (C) (i) 4‐(trifluoromethoxy)phenol, DEAD, PPh₃, THF, 0–20°C, 60 h; (ii) TBAF, THF, 20°C, 0.5–18 h; (iii) I₂, PPh₃, imidazole, CH₂Cl₂, 20°C, 12–35 h; (iv) 97, K₂CO₃, DMF, 90°C, 64–111 h; (v) DDQ, CH₂Cl₂, 20°C, 10–28 h, then TsOH, MeOH, 20°C, 12 h; (vi) NaH, DMF, 0–20°C, 0.25–5.5 h. (D) (i) 1‐fluoro‐4‐(trifluoromethyl)benzene, NaH, DMF, 0–20°C, 0.25–5.5 h

FIGURE 3

In vivo efficacy in the L. infantum hamster model