New pyrrolo[1,2-a]quinoxaline-2-carboxylic acid hydrazone derivatives were synthesized from nitroaniline using a multi-step pathway. Structure characterization of these novel substituted pyrrolo[1,2-a]quinoxaline-carboxylic acid hydrazones was achieved by using FT-IR, 1H NMR, 13C NMR, X-Ray and HRMS spectral analysis. These pyrroloquinoxaline hydrazone compounds were then evaluated in vitro for their potential on the human acute myeloid leukemia cell line MV4-11, in which (N'-pyridin-2-ylmethylene)pyrrolo[1,2-a]quinoxaline-2-carboxylic acid hydrazone 1a showed an IC50 value of 15.51 µM. Given the structural similarities between our hydrazone derivatives 1 and some recently published quinoline-type hydrazone compounds for antimalarial use, our compounds were also evaluated for their antimalarial activity. Among them, compound 1c demonstrated promising antiplasmodial activity, with an IC50 of 0.02 μM against the 3D7 strain of Plasmodium falciparum, exhibiting a selectivity index (SI) exceeding 5000 against this strain. Against the chloroquine-resistant Plasmodium falciparum W2 strain, hydrazone 1e emerged as the most potent and promising antimalarial candidate (IC50 = 0.03 mM), demonstrating a cytotoxicity to-antiprotozoal activity ratio exceeding 3333.

A series of substituted pyrrolo[2,3-d]pyrimidines was designed, synthesized, and evaluated in vitro against two protozoan parasites: Plasmodium falciparum and Trypanosoma brucei brucei. Pharmacological studies revealed antiprotozoal activity with IC50 values in the submicromolar to micromolar range. Additionally, the in vitro cytotoxicity of these new compounds was assessed using human HepG2 cells. Among them, the pyrrolopyrimidine derivative 1d emerged as the most potent antimalarial compound, exhibiting a selectivity index (SI) of 600.81 against the P. falciparum chloroquine-resistant W2 strain. For the chloroquine-sensitive 3D7 strain, the most notable selectivity index (SI) was observed for pyrrolo[2,3-d]pyrimidine 1c, with a value of approximately 123. Furthermore, compound 1b demonstrated the most interesting activity against Trypanosoma brucei brucei, with an SI of 39.52, marking it as a promising trypanocidal agent. FRET melting assays confirmed that these nitrogen-containing heterocyclic compounds bind to telomeric G-quadruplexes in P. falciparum and Trypanosoma. However, no clear correlation was found between G-quadruplex binding and antiparasitic activity or selectivity, suggesting that G-quadruplex targeting is unlikely to be the main mechanism underlying cytotoxicity.

Background: Based on our previously reported series of novel 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene and 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene derivatives, we have now designed, synthesized, and tested a new series of novel restricted and simplified structural analogues of these compounds against Plasmodium falciparum in vitro; i.e., the 1,3-bis[(4-(substituted-aminomethyl)phenyl)methyl]benzene and 1,3-bis[(4-(substituted-aminomethyl)phenoxy)methyl]benzene compounds. Methods & Results: The pharmacological results revealed significant antimalarial activity, with IC50 values in the submicromolar to micromolar range. Additionally, the in vitro cytotoxicity of these new nitrogen-containing polyphenyl- or -phenoxymethylbenzene compounds was evaluated on human HepG2 cells. The compound 1f, the 1,3-bis[(4-(3-(morpholin-1-yl)propyl)aminomethyl)phenoxy)methyl]benzene derivative, emerged as one of the most potent and promising antimalarial candidates, demonstrating a cytotoxicity/antiprotozoal activity ratio of 594 against the chloroquine-sensitive Plasmodium falciparum 3D7 strain. Additionally, the 1,3-bis[((substituted aminomethyl)phenyl)methyl]benzene compound 1j and the 1,3-bis[((substituted aminomethyl)phenoxy)methyl]benzenes 2p and 2q also showed strong antimalarial potential, with selectivity indexes (SI) of over 303, 280, and 217, respectively, against the 3D7 strain, which has mefloquine-reduced sensitivity. Furthermore, the 1,3-bis[(4-(pyridin-2-ylethylaminomethyl)phenyl)methyl]benzene 2k was identified as the most noteworthy antimalarial compound, exhibiting a selectivity index (SI) that was superior to 178 against the chloroquine-resistant Plasmodium falciparum W2 strain. It has previously been suggested that the telomeres of P. falciparum may serve as potential targets for these polyaromatic compounds; thus, we assessed the ability of our novel derivatives to stabilize parasitic telomeric G-quadruplexes using a FRET melting assay. Conclusions: However, regarding the stabilization of the protozoan G-quadruplex, it was noted that the few substituted derivatives, which showed interesting stabilization profiles, were not necessarily the most effective antimalarial compounds against both Plasmodium strains. Moreover, these new compounds did not show promising stabilizing effects on the different G4 sequences. Therefore, no correlation arises between their antimalarial activity and the selectivity of their binding to G-quadruplexes.

By taking into account our previously described series of 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene compounds, we have now designed, prepared, and evaluated in vitro against Plasmodium falciparum a novel series of structural analogues of these molecules, i.e., the 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene derivatives. The pharmacological data showed antimalarial activity with IC50 values in the sub and μM range. The in vitro cytotoxicity of these new nitrogen polyphenoxymethylbenzene compounds was also evaluated on human HepG2 cells. The 1,3,5-tris[(4-(substituted-aminomethyl)phenoxy)methyl]benzene derivative 1m was found as one of the most potent and promising antimalarial candidates with favorable cytotoxic to antiprotozoal properties in the P. falciparum strains W2 and 3D7. In conclusion, this 1,3,5-tris[(4-(pyridin-3-ylmethylaminomethyl)phenoxyl)methyl]benzene 1m (IC50 = 0.07 μM on W2, 0.06 μM on 3D7, and 62.11 μM on HepG2) was identified as the most promising antimalarial derivative with selectivity indexes (SI) of 887.29 on the W2 P. falciparum chloroquine-resistant strain, and of 1035.17 on the chloroquine-sensitive and mefloquine decreased sensitivity strain 3D7. It has been previously described that the telomeres of P. falciparum could represent potential targets for these types of polyaromatic compounds; therefore, the capacity of our novel derivatives to stabilize the parasitic telomeric G-quadruplexes was assessed using a FRET melting assay. However, with regard to the stabilization of the protozoal G-quadruplex, we observed that the best substituted derivatives 1, which exhibited some interesting stabilization profiles, were not the most active antimalarial compounds against the two Plasmodium strains. Thus, there were no correlations between their antimalarial activities and selectivities of their respective binding to G-quadruplexes.

Currently, artemisinin-based combination therapy is recommended as first-line treatment of uncomplicated falciparum malaria. Arylamino alcohols (AAAs) such as mefloquine (MQ) are the preferred partner drugs due to their longer half-life, reliable absorption and strong antimalarial activity. However, the mode of action of MQ remains poorly understood and its neurotoxicity limits its use. Furthermore, the emergence of drug-resistant parasites requires development of new antimalarial drugs. The aim of this study was to evaluate the β-hematin inhibition capacity of three pairs of enantiopure AAAs 1–3 (a/S and b/R) derived from MQ or enpiroline (ENP), a pyridine-based MQ analog with strong antimalarial activity. Inhibition of β-hematin—the synthetic counterpart of hemozoin formation—was determined for each compound. Antimalarial activity against W2 and 3D7 Plasmodium falciparum strains as well as percentages of inhibition of β-hematin formation were compared to those of reference molecules, i.e., chloroquine (CQ), MQ and ENP. Furthermore, a cytotoxicity study on the human-derived hepatocarcinoma cell line HepG2 was performed. With high antimalarial activity, stronger ability to inhibit β-hematin formation and low cytotoxicity, AAAs 1a-b and 2a are the most promising. These findings provide a better understanding of their potential mechanisms of action and may pave the way toward developing new lead compounds.

Herein, we report the design, synthesis, and characterisation of a new library of enantiopure aminoalcohol fluorenes, as well as their in vitro evaluation for biological properties, including activity against two strains of P. falciparum (3D7 and W2) and cytotoxicity on the HepG2 cell line. All tested compounds exhibited good to excellent antimalarial potency with IC50 values ranging from 0.7 to 70.2 nM whatever the strain. Interestingly, most compounds showed equal or better antimalarial activity compared to the reference drugs lumefantrine, mefloquine and chloroquine. Despite moderate cytotoxicity in the micromolar range, all aminoalcohol fluorenes displayed an excellent selectivity index higher than 100 due to strong antimalarial activity. Furthermore, we report in silico analyses of physicochemical and pharmacokinetic properties for all compounds, highlighting the drug-likeness of compound 10 and its promising potential for further studies.

A series of new 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene compounds were designed, synthesized, and evaluated in vitro against two parasites (Plasmodium falciparum and Leishmania donovani). The biological results showed antimalarial activity with IC50 values in the sub and μM range. The in vitro cytotoxicity of these new aza polyaromatic derivatives was also evaluated on human HepG2 cells. The 1,3,5-tris[(4-(substituted-aminomethyl)phenyl)methyl]benzene 1m was found as one of the most potent and promising antimalarial candidates with a ratio of cytotoxic to antiprotozoal activities of 83.67 against the P. falciparum CQ-sensitive strain 3D7. In addition, derivative 1r was also identified as the most interesting antimalarial compound with a selectivity index (SI) of 17.28 on the W2 P. falciparum CQ-resistant strain. It was previously described that the telomeres of P. falciparum could be considered as potential targets of these kinds of aza heterocycles; thus, the ability of these new derivatives to stabilize the parasitic telomeric G-quadruplexes was measured through a FRET melting assay.

Currently artemisinin-based combination therapy is recommended as first-line treatment of uncomplicated falciparum malaria. Arylamino alcohols (AAAs) such as mefloquine (MQ) are the preferred partner drugs due to their longer half-life, reliable absorption and strong antimalarial activity. However, the mode of action of MQ remains poorly understood and its neurotoxicity limits its use. Furthermore, the emergence of drug-resistant parasites requires continuous research and development of new antimalarial drugs. In this context, the development of enantiopure AAAs derived from MQ, exhibiting strong activity against resistant strains, good pharmacokinetic profiles and with an identified mode of action seems particularly interesting. The aim of this study was to evaluate the β-hematin inhibition capacity of three pairs of enantiopure AAAs 1-3 (a/S and b/R) derived from MQ or enpiroline (ENP), a pyridine-based MQ analog with a strong antimalarial activity. Compounds 1-3 have a different aromatic core substituted by the same butyl chain: quinoline core for MQ-derived compounds 1a-b and pyridine core for ENP-derived compounds 2a-b and 3a-b. Inhibition of β-hematin (the synthetic counterpart of hemozoin) formation was determined for each compound at 2 mM. Antimalarial activity determined on W2 and 3D7 Plasmodium falciparum strains as well as percentages of inhibition of β-hematin formation were compared to that of reference molecules, i.e. chloroquine (CQ), MQ and ENP. Furthermore, a cytotoxicity study on the human-derived hepatocarcinoma cell line HepG2 was performed on the most active compounds to determine their selectivity index (SI). With high antimalarial activity, stronger ability to inhibit β-hematin formation and low cytotoxicity, AAAs 1a-b and 2a are the most promising. These findings provide a better understanding of potential mechanisms of action of these MQ and ENP analogs and may pave the way toward developing new lead compounds.

In order to fight malaria, a public health problem for which nearly half of the world's population is at risk and responsible a lifethreatening disease primarily found in tropical countries and for which the estimated number of deaths stood at 619 000 in 2021, an original strategy is to design and synthesize quinoline-based drugs that are not recognized by the protein system involved in the drug efflux.Thus, a series of new 2,6-di-(carbamoyl-2-quinolinyl)pyridine derivatives was considered, synthesized, and evaluated in vitro against three parasites (Plasmodium falciparum, Leishmania donovani and Trypanosoma brucei brucei).Pharmacological results showed antiparasitic activity with IC 50 values in the sub and µM range.The in vitro cytotoxicity of these new diquinolinyl-pyridine derivatives was evaluated on human HepG2 cells.The diquinolinyl-pyridine 1e was found as the most potent antimalarial candidate with a ratio of cytotoxic to antiprotozoal activities of 73.5 against the P. falciparum CQ-resistant strain W2.Moreover, derivative 3b was also identified as the most potent antiparasitic compound with a selectivity index (SI) of 21.48 on 3D7 P. falciparum CQsensitive strain.In addition, the 2,6-di-(carbamoyl-2-quinolinyl)pyridines 2c and 3b were also identified as the most interesting antitrypanosomal candidate drugs with selectivity index (SI) of 75.9 and 38.94, respectively on T. brucei brucei strain.It has been previously described that the telomeres of parasites P. falciparum and Trypanosoma could be considered as potential targets of this kind of nitrogen heterocycles, thus the ability of these new derivatives to stabilize the parasitic telomeric G-quadruplexes have been measured through a FRET melting assay.

A series of new 2,9-bis[(pyridinylalkylaminomethyl)phenyl]-1,10-phenanthroline compounds was considered, synthesized, and evaluated in vitro against three parasites (Plasmodium falciparum, Leishmania donovani and Trypanosoma brucei brucei).Pharmacological results showed antiparasitic activity with IC 50 values in the sub and µM range.The in vitro cytotoxicity of these novel aza derivatives was evaluated on human HepG2 cells.The phenanthroline 1f was noticed as the most potent antimalarial candidate with a ratio of cytotoxic to antiprotozoal activities of 912.4 against the P. falciparum CQ-resistant strain W2.In addition, the phenanthroline 1a was also identified as the most potent antiparasitic derivative with a selectivity index (SI) of 811.8 on P. falciparum CQ-sensitive strain 3D7.Against the promastigote forms of L. donovani, the same phenanthroline 1a was found the most active compounds with an IC 50 of 2.08 mM.In addition, the phenanthrolines 1f and 1i were also identified as the most promising trypanosomal candidates with selectivity index (SI) of 231.1 and 143.7, respectively on T. brucei brucei strain.As the telomeres of the parasites P. falciparum and Trypanosoma could be considered as possible targets of this kind of aza heterocyclic molecules, their ability to stabilize the parasitic telomeric G-quadruplexes have been measured through the FRET melting assay.

Malaria is the fifth most lethal parasitic infections in the world. Herein, five new series of aminoalcohol quinolines including fifty-two compounds were designed, synthesized and evaluated in vitro against Pf3D7 and PfW2 strains. Among them, fourteen displayed IC50 values below or near of 50.0 nM whatever the strain with selectivity index often superior to 100.17b was found as a promising antimalarial candidate with IC50 values of 14.9 nM and 11.0 nM against respectively Pf3D7 and PfW2 and a selectivity index higher than 770 whatever the cell line is. Further experiments were achieved to confirm the safety and to establish the preliminary ADMET profile of compound 17b before the in vivo study performed on a mouse model of P. berghei ANKA infection. The overall data of this study allowed to establish new structure-activity relationships and the development of novel agents with improved pharmacokinetic properties.

A series of novel 2,9-bis[(substituted-aminomethyl)]-4,7-phenyl-1,10-phenanthroline derivatives was designed, synthesized, and evaluated in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani and Trypanosoma brucei brucei). Pharmacological results showed antiprotozoal activity with IC50 values in the sub and μM range. In addition, the in vitro cytotoxicity of these original molecules was assessed with human HepG2 cells. The substituted diphenylphenanthroline 1l was identified as the most potent antimalarial derivative with a ratio of cytotoxic to antiparasitic activities of 505.7 against the P. falciparum CQ-resistant strain W2. Against the promastigote forms of L. donovani, the phenanthrolines 1h, 1j, 1n and 1o were the most active with IC50 from 2.52 to 4.50 μM. The phenanthroline derivative 1o was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 91 on T. brucei brucei strain. FRET melting and native mass spectrometry experiments evidenced that the nitrogen heterocyclic derivatives bind the telomeric G-quadruplexes of P. falciparum and Trypanosoma. Moreover, as the telomeres of the parasites P. falciparum and Trypanosoma could be considered to be possible targets of this kind of nitrogen heterocyclic derivatives, their potential ability to stabilize the parasitic telomeric G-quadruplexes have been determined through the FRET melting assay and by native mass spectrometry.

Malaria still is one of the most threatening diseases in the world. In 2019, the WHO estimated 229 million of cases and 409,000 deaths mainly due to the most prevalent and lethal Plasmodium species: P. falciparum (Pf). Fighting resistant Pf strains is henceforth one of the main challenges to eradicate malaria. Indeed, parasites have developed resistances against all the available therapeutic arsenal, including artemisinin-based combination therapies (ACT). Studies of resistance phenotypes identified efflux pumps involved in this phenomenom of which the multidrug resistance ABC transporter PfMDR1. Its overexpression is partly responsible of the carrying of two ACT partner drugs, mefloquine (MQ) and lumefantrine (LM), into the food vacuole away from their cytosolic targets, leading to the efficacy decline of these arylaminoalcohol drugs. In order to limit this efflux, our laboratory has developed efflux pump inhibitor (EPI) patterns based on previous described resistance reversing agents such as penfluridol. A library of novel arylaminoalcohols is easily affordable into a previously optimized synthesis to obtain MQ, LM and enpiroline analogs. This stereoselective and convergent synthesis requires a key arylvinyl converted to the corresponding enantiopure aryloxirane thanks to a Sharpless asymmetric dihydroxylation followed by a one-pot cyclization. Finally, a regioselective ring-opening by EPI moieties led to efflux pump substrate compounds. Both design and synthesis of these arylaminoalcohols will be herein presented. In vitro efficacy against two Pf strains, cytotoxicity and preliminary results of P-gp, BCRP and MRPs efflux modulation in Caco-2 cells model will be reported. First structure-activity relationships will be discussed.

We describe the enantioselective synthesis and biological evaluation of 4-(2-amino-l-hydroxyethyl) pyridines (4 AHPs) as new antimalarial drug candidates. In particular, two routes to obtain the key-intermediate 4-vinyl-pyridine were studied. These routes are based on a Krohnke-type cyclization or on metal-catalyzed reactions. The Krohnke-type cyclization route is faster but only efficient at low scale since this pathway involves a Wittig reaction that requires severe temperature-control. Consequently, we designed a second route based on metal-catalyzed reactions. This way is longer but the 4-vinyl-pyridine can be obtained on a 5 g scale at least. Finally, a regioselective S(N)2 ring-opening of enantiopure epoxides by alkyl primary amines allowed the synthesis of eight 4-AHPs with global yields up to 41%. These compounds show strong in vitro antimalarial activity against P. falciparum strains and are more active that chloroquine and mefloquine. These results demonstrate that 4-AHPs are promising antimalarial drug candidates. (C) 2020 Elsevier Ltd. All rights reserved.

A series of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline, and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives was designed, synthesised, and evaluated in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiprotozoal activity with IC50 values in the µM range. In addition, the in vitro cytotoxicity of these original molecules was assessed with human HepG2 cells. The quinoline 1c was identified as the most potent antimalarial candidate with a ratio of cytotoxic to antiparasitic activities of 97 against the P. falciparum CQ-sensitive strain 3D7. The quinazoline 3h was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 43 on T. brucei brucei strain. Moreover, as the telomeres of the parasites P. falciparum and Trypanosoma are possible targets of this kind of nitrogen heterocyclic compounds, we have also investigated stabilisation of the Plasmodium and Trypanosoma telomeric G-quadruplexes by our best compounds through FRET melting assays.

Many cities in developing countries are facing serious problems of microbiological quality of their water resources. In this context, chlorination is used as common method of treating water intended for human consumption. However, it has been shown that disinfection by chlorination is ineffective in inactivating Cryptosporidium oocysts. Therefore, the physicochemical behavior of Cryptosporidium oocysts and geological formation of those areas become an important environmental issue of research. In Haiti, Cryptosporidium oocysts have been identified in the groundwater being used for human consumption in Les Cayes. Moreover, cryptosporidiosis is one of the most frequent causes of diarrhea in Haiti. The transfer of Cryptosporidium oocysts, through an alluvial formation from Les Cayes (Haiti), was investigated. The aim of this chapter was (i) to review the biological cycle of Cryptosporidium and the physicochemical behavior of Cryptosporidium oocysts in order (ii) to understand their movement through soils and (iii) to evaluate the chemical conditions and soil characteristics which can constitute factors influencing the retention of oocysts or facilitate their transfer into groundwater.

To date, malaria still remains as one of the most threatening diseases in the world with 228 million of cases in 2018. The causative agents are Plasmodium parasites, among which P. falciparum (Pf) is the most virulent and common for human infection. The main challenge of the fight against malaria is the parasite resistance to antimalarial medicines. Despite the World Health Organization recommendations for preventing and reducing this risk with artemisinin-based combination therapy, more and more parasites are emerging with both decreased sensibility to artemisinin derivatives and resistance to the partner drug. Mefloquine (MQ) and lumefantrine (LM) are one of the most used partners with artesunate and artemether respectively. However, genic mutations or overexpression of efflux pumps in Pf are responsible of their decreased antimalarial efficacy. Thus, covalent conjugation of their respective structure with efflux pump inhibitors (EPI) or reversal agents can allow to struggle resistant parasites. Our laboratory has previously developed an asymmetric synthesis to prepare 4-aminoalcohol-quinoline and -fluorene as enantiopure MQ and LM analogs. Some of them were active on nanomolar range against Pf3D7 (chloroquine-sensitive) and PfW2 (chloroquine-resistant) with a good selectivity index. Interestingly, eudysmic ratio was often observed between the enantiomers. Follow this previous work, we are focus on conjugation of EPI patterns to develop new classes of 4-aminoalcohol-quinolines and -fluorenes as enantiopure hybrid compounds able to limit the resistance with efflux transporters. The design of these hybrids will be discussed and described. First results concerning their biological activity against Pf3D7 and PfW2 and their cytotoxicity will be debated.