Synthesis of new piperazinyl-pyrrolo[1,2-a]quinoxaline derivatives as inhibitors of Candida albicans multidrug transporters by a Buchwald–Hartwig cross-coupling reaction

Abstract

Two series of piperazinyl-pyrrolo[1,2-a]quinoxaline derivatives were prepared via a Buchwald-Hartwig cross-coupling reaction and then evaluated for their ability to inhibit the drug efflux activity of CaCdr1p and CaMdr1p transporters of Candida albicans overexpressed in a Saccharomyces cerevisiae strain. In the initial screening of twenty-nine piperazinyl-pyrrolo[1,2-a]quinoxaline derivatives, twenty-three compounds behaved as dual inhibitors of CaCdr1p and CaMdr1p. Only four compounds showed exclusive inhibition of CaCdr1p or CaMdr1p. Further biological investigations were developed and for example, their antifungal potential was evaluated by measuring the growth of control yeast cells (AD1-8u À ) and efflux pump-overexpressing cells (AD-CDR1 and AD-MDR1) after exposition to variable concentrations of the tested compounds. The MIC 80 values of nineteen compounds ranging from 100 to 901 mM for AD-CDR1 demonstrated that relative resistance index (RI) values were between 8 and 274. In comparison, only seven compounds had RI values superior to 4 in cells overexpressing Mdr1p. These results indicated substrate behavior for nineteen compounds for CaCdr1p and seven compounds for CaMdr1p, as these compounds were transported via MDR transporter overexpressing cells and not by the AD1-8u À cells. Finally, in a combination assay with fluconazole, two compounds (1d and 1f) have shown a synergistic effect (fractional inhibitory concentration index (FICI) values # 0.5) at micromolar concentrations in the AD-MDR1 yeast strain overexpressing CaMdr1p-protein, indicating an excellent potency toward chemosensitization. Scheme 1 Synthesis of 1-(4-substituted-piperazinyl)-4-phenylpyrrolo[1,2-a]quinoxalines 1a-i; reagents and conditions: (i) 2,5-diMeOTHF, AcOH, D; (ii) CuSO 4 /NaBH 4 , EtOH, RT; (iii) (Cl 3 CO) 2 Fig. 2 The ORTEP drawing of pyrrolo[1,2-a]quinoxaline 1a with thermal ellipsoids at 30% level.This journal is Fig. 3 The ORTEP drawing of pyrrolo[1,2-a]quinoxaline 1h (molecules A and B) with thermal ellipsoids at 30% level. 2920 | RSC Adv., 2020, 10, 2915-2931 This journal is Scheme 2 Synthesis of 4-(4-substituted-piperazinyl)-4-phenylpyrrolo[1,2-a]quinoxalines 1j-w; reagents and conditions: (i) R-piperazine, Pd 2 (dba) 3 , BINAP, t-BuONa, toluene, 100 C. This journal is Scheme 3 Synthesis of piperazinylalcohol-pyrrolo[1,2-a]quinoxalines 2a-e; reagents and conditions: (i) K 2 CO 3 , DMF, 120 C. 2922 | RSC Adv., 2020, 10, 2915-2931 This journal is Scheme 4 Synthesis of piperazinylalcohol-pyrrolo[1,2-a]quinoxaline 2f; reagents and conditions: (i) (C 6 H 5 ) 2 CH-piperazine, isopropanol, D. This journal isView Article Online a Evaluated by the checkerboard method, and expressed as the fractional inhibitory concentration (FIC) values for the uconazole (¼MIC 80 of uconazole in combination/MIC 80 of uconazole alone). b Each compound (¼MIC 80 of compound in combination/MIC 80 of compound alone). The values in brackets are expressed in mM. c FIC index (FICI) value #0.5 indicates synergistic interaction between the compound and t...

Structure, function, and inhibition of catalytically asymmetric ABC transporters: Lessons from the PDR subfamily

“…Quinoxaline bearing piperazinyl moieties were identified as dual inhibitors of CaCdr1 and CaMdr1 overexpressed in a Saccharomyces cerevisiae strain (Guillon et al, 2020).…”

Synthesis of Functionalized 3H-pyrrolo-[1,2,3-de] Quinoxalines via Gold-Catalyzed Intramolecular Hydroamination of Alkynes

“…Extensive state-of-the-art studies revealed a lack of methods to achieve their construction, even though their synthesis might be of interest in medicinal chemistry. Indeed, the tricyclic quinoxaline-containing compounds are widespread in a variety of therapeutic agents such as anti-HIV [10], antiparasitic [11][12][13][14], and antitumoral [15] (Figure 1), and make our new condensed cyclic systems promising candidates for diverse uses. To the best of our knowledge, the derivatives of which the synthesis was pursued are unknown compounds with a rather infrequently reported heterocyclic core [8,9].…”

Carbonylative Synthesis of Fused Quinoxalinones via Palladium-Catalyzed Cascade Cyclization of 2-Heteroaryl Iodobenzene and NaN3

“…2 For instance, the piperazinyl-pyrrolo [1,2-a]quinoxaline derivatives could be used as inhibitors of Candida albicans multidrug transporters. 3 Therefore, the development of facile and direct methods for the assembly of the kind of valuable heterocycles is of great significance.…”

“… Moreover, the privileged compounds are frequently applied as key intermediates or precursors to build other useful heterocycles possessing interesting biological activities . For instance, the piperazinyl-pyrrolo­[1,2- a ]­quinoxaline derivatives could be used as inhibitors of Candida albicans multidrug transporters . Therefore, the development of facile and direct methods for the assembly of the kind of valuable heterocycles is of great significance.…”