Synthesis and Antiplasmodial Activity of Novel Fosmidomycin Derivatives and Conjugates with Artemisinin and Aminochloroquinoline.

Malaria, despite many efforts, remains among the most problematic infectious diseases worldwide, mainly due to the development of drug resistance by Plasmodium falciparum. The antibiotic fosmidomycin (FSM) is also known for its antimalarial activity by targeting the non-mevalonate isoprenoid synthesis pathway, which is essential for the malaria parasites but is absent in mammalians. In this study, we synthesized and evaluated against the chloroquine-resistant P. falciparum FcB1/Colombia strain, a series of FSM analogs, derivatives, and conjugates with other antimalarial agents, such as artemisinin (ART) and aminochloroquinoline (ACQ). The biological evaluation revealed four new compounds with higher antimalarial activity than FSM: two FSM-ACQ derivatives and two FSM-ART conjugates, with 3.5-5.4 and 41.5-23.1 times more potent activities than FSM, respectively.

Synthesis of Novel G Factor or Chloroquine-Artemisinin Hybrids and Conjugates with Potent Antiplasmodial Activity.

A series of novel hybrids of artemisinin (ART) with either a phytormone endoperoxide G factor analogue (GMeP) or chloroquine (CQ) and conjugates of the same compounds with the polyamines (PAs), spermidine (Spd), and homospermidine (Hsd) were synthesized and their antiplasmodial activity was evaluated using the CQ-resistant P. falciparum FcB1/Colombia strain. The ART-GMeP hybrid 5 and compounds 9 and 10 which are conjugates of Spd and Hsd with two molecules of ART and one molecule of GMeP, were the most potent with IC50 values of 2.6, 8.4, and 10.6 nM, respectively. The same compounds also presented the highest selectivity indexes against the primary human fibroblast cell line AB943 ranging from 16 372 for the hybrid 5 to 983 for the conjugate 10 of Hsd.

Synthesis, In Silico, and In Vitro Evaluation of Anti-Leishmanial Activity of Oxadiazoles and Indolizine Containing Compounds Flagged against Anti-Targets.

Due to the lack of approved vaccines against human leishmaniasis and the limitations of the current chemotherapy inducing side effects and drug resistance, development of new, effective chemotherapeutic agents is essential. This study describes the synthesis of a series of novel oxadiazoles and indolizine-containing compounds. The compounds were screened in silico using an EIIP/AQVN filter followed by ligand-based virtual screening and molecular docking to parasite arginase. Top hits were further screened versus human arginase and finally against an anti-target battery to tag their possible interactions with proteins essential for the metabolism and clearance of many substances. Eight candidate compounds were selected for further experimental testing. The results show measurable in vitro anti-leishmanial activity for three compounds. One compound with an IC50 value of 2.18 µM on Leishmania donovani intramacrophage amastigotes is clearly better positioned than the others as an interesting molecular template for further development of new anti-leishmanial agents.

A revisited structure for nitrosoprodenafil from NMR, mass spectrometry, X-ray and hydrolysis data.

The sildenafil analogue adulterant previously identified as a nitroso derivative (nitrosoprodenafil) in a dietary supplement (DS) marketed to increase sexual performance and sold in Europe in the early 2010s is the same as that found in the same type of DS available in Japan whose structure was established as a nitro derivative (mutaprodenafil or nitroprodenafil). Indeed, the compound isolated from the Man Power DS has identical UV, IR, NMR and MS spectroscopic characteristics and hydrolysis behavior than nitrosoprode-nafil. By revisiting its NMR assignments and MS and MS/MS data interpretation, it is demonstrated that the compound is actually a nitrothioimidazole-methisosildenafil hybrid, i.e. nitroprodenafil, whose structure is unequivocally confirmed by X-ray crystallography and synthesis experiments. Because the product is converted to methisosildenafil by hydrolysis, it is named nitropromethisosildenafil.

Pyrrolidinone and pyrrolidine derivatives: Evaluation as inhibitors of InhA and Mycobacterium tuberculosis.

A series of GEQ analogues bearing pyrrolidinone or pyrrolidine cores were synthesized and evaluated against InhA, essential target for Mycobacterium tuberculosis (M.tb) survival. The compounds were also evaluated against M.tb H37Rv growth. Interestingly, some of the compounds, not efficient as InhA inhibitors, are active against M.tb with MICs up to 1.4 µM. In particular, compound 4b was screened with different M.tb mutated strains in order to identify the cellular target, but without success, suggesting a new possible mode of action.

Design, synthesis and evaluation of new GEQ derivatives as inhibitors of InhA enzyme and Mycobacterium tuberculosis growth.

A series of fluorene-based derivatives was synthesized and evaluated for inhibiting both InhA and Mycobacterium tuberculosis growth. These compounds were inspired by the previously reported Genz-10850 molecule, a good InhA inhibitor, but with a poor activity against M. tuberculosis growth. Structure-activity relationships were performed by introducing the following chemical modifications: 1) the piperazine ring; 2) the amide group; 3) the aryl moiety; and 4) the fluorene moiety. Among these new derivatives, one of them was more effective against both the InhA activity and mycobacterial growth, compared to the hit compound. Docking studies were also performed to rationalize activities of these derivatives. Furthermore, we showed for the first time that efflux pump inhibitors potentiated the efficacy of Genz-10850 (GEQ) derivatives against M. tuberculosis growth, demonstrating that these compounds could be substrates of some efflux pumps.

Synthesis and evaluation of α-ketotriazoles and α,ß-diketotriazoles as inhibitors of Mycobacterium tuberculosis.

Two series of α-ketotriazole and α,ß-diketotriazole derivatives were synthesized and evaluated for antitubercular and cytotoxic activities. Among them, two α,ß-diketotriazole compounds, 6b and 9b, exhibited good activities (minimum inhibitory concentration = 7.6 µM and 6.9 µM, respectively) on Mycobacterium tuberculosis and multi-drug resistant M. tuberculosis strains and presented no cytotoxicity (IC50 > 50 µM) on colorectal cancer HCT116 and normal fibroblast GM637H cell lines. These two compounds represent promising leads for further optimization.

Chemical synthesis and biological evaluation of triazole derivatives as inhibitors of InhA and antituberculosis agents.

A series of triazoles have been prepared and evaluated as inhibitors of InhA as well as inhibitors of Mycobacterium tuberculosis H(37)R(v). Several of these new compounds possess a good activity against InhA, particularly compounds 17 and 18 for which molecular docking has been performed. Concerning their activities against M. tuberculosis H(37)R(V) strain, two of them, 3 and 12, were found to be good inhibitors with MIC values of 0.50 and 0.25 µg/mL, respectively. Particularly, compound 12 presenting the best MIC value of all compounds tested (0.6 µM) is totally inactive against InhA.

Synthesis and biological activities of triazole derivatives as inhibitors of InhA and antituberculosis agents.

InhA, the enoyl reductase from the mycobacterial type II fatty acid biosynthesis pathway, is a target for the development of novel drugs against tuberculosis. We exploited copper-catalyzed [3+2] cycloaddition between alkynes and different azides to afford 1,4-disubstituted triazole or α-ketotriazole derivatives. Several compounds bearing a lipophilic chain mimicking the substrate were able to inhibit InhA. Among them, 1-dodecyl-4-phenethyl-1H-1,2,3-triazole displayed a minimum inhibitory concentration inferior to 2 µg/mL against Mycobacterium tuberculosis H37Rv.

Meroterpenes from Dichrostachys cinerea inhibit protein farnesyl transferase activity.

Eighteen new meroterpene derivatives, dichrostachines A-R (1-18), have been isolated from the root and stem barks of Dichrostachys cinerea, and their structures determined by spectroscopic means and molecular modeling. From a biosynthetic standpoint these compounds arise from a Diels-Alder reaction between a labdane diene of the raimonol type and a flavonoid B-ring-derived quinone. The hypothesis was tested by the partial synthesis of similar compounds by simply mixing methyl communate and a synthetic flavonoid quinone. The hemisynthetic compounds were shown by NMR to have configurations different from those of the natural products, thus allowing a refinement of the biosynthesis hypothesis. Most of the compounds were assayed for their ability to inhibit the enzyme protein farnesyl transferase. The most active compounds exhibited IC50 and cytotoxicity values in the 1 microM range.