Indole-Containing Pyrazino[2,1-b]quinazoline-3,6-diones Active against Plasmodium and Trypanosomatids

Abstract

Malaria, leishmaniasis, and sleeping sickness are potentially fatal diseases that represent a real health risk for more than 3,5 billion people. New antiparasitic compounds are urgent leading to a constant search for novel scaffolds. Herein, pyrazino­[2,1-b]­quinazoline-3,6-diones containing indole alkaloids were explored for their antiparasitic potential against Plasmodium falciparum, Trypanosoma brucei, and Leishmania infantum. The synthetic libraries furnished promising hit compounds that are species specific (7, 12) or with broad antiparasitic activity (8). Structure–activity relationships were more evident for Plasmodium with anti-isomers (1S,4R) possessing excellent antimalarial activity, while the presence of a substituent on the anthranilic acid moiety had a negative effect on the activity. Hit compounds against malaria did not inhibit β-hematin, and in silico studies predicted these molecules as possible inhibitors for prolyl-tRNA synthetase both from Plasmodium and Leishmania. These results disclosed a potential new chemotype for further optimization toward novel and affordable antiparasitic drugs.

Fiscalin Derivatives as Potential Neuroprotective Agents

“…Compound 1a was previously synthesized in our laboratory, via Mazurkiewicz–Ganesan approach, consisting of coupling of linear tripeptides follow by isomerization of 4-imino-4 H -3,1-benzoxozines to obtain the corresponding quinazolin-4-ones of 1a , 3 and 4 ( Scheme 1 Method A) by removing a protecting group. Derivatives 1b , 1c , 2a , 2b and 5 – 15 were also previously obtained using a microwave-assisted multicomponent one-step polycondensation of amino acids [ 30 , 32 , 33 , 38 , 39 , 40 ]. The procedure was summarized as a condensation of N -protected α-amino acids with anthranilic acids under mild heating with triphenylphosphite (PhO) 3 P, generating the intermediate benzoxazine-4-one, followed by flash microwave irradiation with tryptophan ester to yield the desired products ( Scheme 1 Method B).…”

“…Indole-coquinazolinone-3,6-(4H)-diones compounds 1a , 1b , 1c , 2a , 2b , 3 – 15 were previously synthesized and used without further purification after purity assessment [ 30 , 32 , 33 , 38 , 39 , 40 ]: (1 S ,4 S )-4-(1H-Indol-3-ylmethyl)-1-isopropyl-2H-pyrazino[2,1-b] quinazolin-3,6-(1H, 4H)-dione ( 1a ), (1 R ,4 S )-4-(1H-Indol-3-ylmethyl)-1-isopropyl-2H-pyrazino[2,1-b]quinazoline-3,6-(1H,4H)-dione ( 1b ), (1 S ,4 R )-4-(1H-Indol-3-ylmethyl)-1-isopropyl-2H-pyrazino[2,1-b]quinazoline-3,6-(1H,4H)-dione ( 1c ), (1 R ,4 S )-4-(1H-Indol-3-ylmethyl)-1-isobutyl-2H-pyrazino[2,1-b]quinazoline-3,6-(1H,4H)-dione ( 2a ), (1 S ,4 R )-4-(1H-Indol-3-ylmethyl)-1-isobutyl-2H-pyrazino[2,1-b]quinazoline-3,6-(1H,4H)-dione ( 2b ) [ 38 ]. (1 S ,4 R )-4-((1H-indol-3-yl)methyl)-1-(2-(methylthio)ethyl)-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-diones ( 3 ), (1 S ,4 S )-4-((1H-indol-3-yl)methyl)-1-(4-hydroxybenzyl)-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione ( 4 ), (1 R ,4 S )-4-((1H-indol-3-yl)methyl)-1-(4-hydroxybenzyl)-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione ( 5 ) [ 30 ], (1 S ,4 R )-4-((1H-indol-3-yl)methyl)-8-hydroxy-1-isobutyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione ( 6 ), (1 S ,4 R )-4-((1H-indol-2-yl)methyl)-1-isobutyl-9-(1-methyl-1H-tetrazol-5-yl)-1,2-dihydro-6H-pyrazino [2,1-b]quinazoline-3,6(4H)-dione ( 7 ), (1 S ,4 R )-4-((1H-indol-3-yl)methyl)-1-isobutyl-8-methoxy-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione ( 8 ), (7 R ,10 S )-7-((1H-indol-3-yl)methyl)-10-isobutyl-9,10-dihydro-5H-pyrazino[1,2-a]pyrido[2,3-d]pyrimidine-5,8(7H)-dione ( 9 ) [ 33 ], (1 S ,4 R )-4-((1H-indol-3-yl)methyl)-8-chloro-1-isopropyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione ( 10 ), (1 S ,4 R )-4-((1H-indol-3-yl)methyl)-8-chloro-1-isobutyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione ( 11 ) [ 32 ], (1 S ,4 R )-4-((1H-indol-3-yl)methyl)-1-(4-(benzyloxy)benzyl)-8,10-dichloro-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione ( 12 ) [ 30 ], (1 S ,4 R )-4-((1H-indol-3-yl)methyl)-8-iodo-1-isopropyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione ( 13 ), (1 S ,4 R )-4-((1H-indol-3-yl)methyl)-8-bromo-1-isopropyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione ( 14 ), (1 S ,4 R )-4-((1H-indol-3-yl)methyl)-8,10-diiodo-1-isobutyl-1,2-dihydro-6H-pyrazino[2,1-b]quinazoline-3,6(4H)-dione ( 15 ) […”

“…The procedure was summarized as a condensation of N-protected α-amino acids with anthranilic acids under mild heating with triphenylphosphite (PhO) 3 P, generating the intermediate benzoxazine-4-one, followed by flash microwave irradiation with tryptophan ester to yield the desired products (Scheme 1 Method B). Indole-coquinazolinone-3,6-(4H)-diones compounds 1a, 1b, 1c, 2a, 2b, 3-15 were previously synthesized and used without further purification after purity assessment [30,32,33,[38][39][40]: (15) [32].…”

“…In fact, substance P inhibitors were already reported to have neuroprotective properties by using a 6-hydroxydopamine model of PD [ 29 ], and some fiscalin derivatives obtained by synthesis by Long et al showed neuroprotective properties in SH-SY5Y cells treated with rotenone [ 30 ]. Moreover, other studies have shown that fiscalins also have antimicrobial [ 27 , 31 , 32 , 33 ], anticancer [ 27 , 34 , 35 , 36 , 37 ] and neuroprotective [ 30 ] properties.…”

A recent update on new synthetic chiral compounds with antileishmanial activity

“…52,53 Recently, Nogueira, Sousa and co-workers studied the activity of indoles having a pyrazino[2,1-b]quinazoline-3,6-dione functionality against Plasmodium falciparum, T. brucei, and L. infantum. 54 The synthesis of the most active compound 53 is reported in Scheme 7 55 and essentially followed a Mazurkiewicz-Ganesan approach. 56 The reaction of 2-aminobenzoic acid 47 with methyl D-tryptophanate 48, followed by a two-phase Schotten-Baumann reaction with D-leucine chloride 50 57 yielded the tripeptides 51.…”