Design,synthesis and antimalarial activity of novel bis{N-[(pyrrolo[1,2-a]quinoxalin-4-yl)benzyl]-3-aminopropyl}amine derivatives

Novel series of bis- and tris-pyrrolo[1,2-a]quinoxaline derivatives 1 were synthesized and tested for in vitro activity upon the intraerythrocytic stage of W2 and 3D7 Plasmodium falciparum strains. Biological results showed good antimalarial activity with IC₅₀ in the μM range. In attempting to investigate the large broad-spectrum antiprotozoal activities of these new derivatives, their properties toward Leishmania donovani were also investigated and revealed their selective antiplasmodial profile. In parallel, the in vitro cytotoxicity of these molecules was assessed on the human HepG2 cell line. Structure–activity relationships of these new synthetic compounds are discussed here. The bis-pyrrolo[1,2-a]quinoxalines 1n and 1p were identified as the most potent antimalarial candidates with selectivity index (SI) of 40.6 on W2 strain, and 39.25 on 3D7 strain, respectively. As the telomeres of the parasite could constitute an attractive target, we investigated the possibility of targeting Plasmodium telomeres by stabilizing the Plasmodium telomeric G-quadruplexes through a FRET melting assay by our new compounds.     

Evaluation of naphthoquinones identified the acetylated isolapachol as a potent and selective antiplasmodium agent

Abstract

This study reports on the design, synthesis and antiparasitic activity of three new semi-synthetic naphthoquinones structurally related to the naturally-occurring lapachol and lapachone. Of the compounds tested, 3-(3-methylbut-1-en-1-yl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl acetate (1) was the most active against Plasmodium falciparum among both natural and semi-synthetic naphthoquinones, showing potent and selective activity. Compound 1 was able to reduce the in vitro parasite burden, in vitro parasite cell cycle, as well as the blood parasitemia in Plasmodium berghei-infected mice. More importantly, infection reduction under compound 1-treatment was achieved without exhibiting mouse genotoxicity. Regarding the molecular mechanism of action, this compound inhibited the hemozoin crystal formation in P. falciparum treated cells, and this was further confirmed by observing that it inhibits the β-hematin polymerization process similarly to chloroquine. Interestingly, this compound did not affect either mitochondria structure or cause DNA fragmentation in parasite treated cells. In conclusion, we identified a semi-synthetic antimalarial naphthoquinone closely related to isolapachol, which had stronger antimalarial activity than lapachol.     

Antimalarial activity of anthothecol derived from Khaya anthotheca (Meliaceae)

Antimalarial activity of anthothecol, a limonoid of Khaya anthotheca (Meliaceae) against Plasmodium falciparum was tested using a [³H]-hypoxanthine and 48 h culture assay in vitro. Anthotechol showed potent antimalarial activity against malaria parasites with IC₅₀ values of 1.4 and 0.17 μM using two different assays. Also, gedunin had antimalarial activity with IC₅₀ values of 3.1 and 0.14 μM. However, the citrus limonoids, limonin and obacunone did not show any antimalarial activity. The antimalarial activities were compared with the three currently used antimalarial medicines quinine, chloroquinine and artemisinin.     

Design,synthesis, and antiprotozoal evaluation 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

Abstract

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.     

Lagunamide C, a cytotoxic cyclodepsipeptide from the marine cyanobacterium Lyngbya majuscula

Lagunamide C (1) is a cytotoxic cyclodepsipeptide isolated from the marine cyanobacterium, Lyngbya majuscula, from the western lagoon of Pulau Hantu Besar, Singapore. The complete structural characterization of the molecule was achieved by extensive NMR spectroscopic analysis as well as chemical manipulations. Several methods, including the advanced Marfey’s method, a modified method based on derivatization with Mosher’s reagents and analysis using LC–MS, and the use of ³J_H–H coupling constant values, were utilized for the determination of its absolute configuration. Compound 1 is related to the aurilide-class of molecules and it differs mainly in the macrocyclic structure by having a 27 membered ring system due to additional methylene carbon in the polyketide moiety. Lagunamide C displayed potent cytotoxic activity against a panel of cancer cell lines, such as P388, A549, PC3, HCT8, and SK-OV3 cell lines, with IC₅₀ values ranging from 2.1 nM to 24.4 nM. Compound 1 also displayed significant antimalarial activity with IC₅₀ value of 0.29 μM when tested against Plasmodium falciparum. In addition, lagunamide C exhibited weak anti-swarming activity when tested at 100 ppm against the Gram-negative bacterial strain, Pseudomonas aeruginosa PA01.     

Novel pyrazole–pyrazoline hybrids endowed with thioamide as antimalarial agents: their synthesis and 3D-QSAR studies

Abstract

One of the most viable options to tackle the growing resistance to the antimalarial drugs is hybrid molecules. It involves combination of different scaffolds in one frame that may lead to compounds with diverse biological profiles. In this context, new hybrids of three different scaffolds viz pyrazole, pyrazoline and thiosemicarbazone moiety were incorporated into one single compound and evaluated for their in vitro schizontocidal activity against the CQ-sensitive 3D7 strain of Plasmodium falciparum. Compounds with significant in vitro antimalarial activity were further evaluated for cytotoxicity against VERO cell lines. The best active compound 48 exhibited an IC₅₀ of 1.13?µM. The in vitro results were further validated by quantitative structure–activity relationship (QSAR).     

Synthesis and antimalarial activity of new chloroquine analogues carrying a multifunctional linear side chain

We report the synthesis and in vitro antimalarial activity of several new 4-amino- and 4-alkoxy-7-chloroquinolines carrying a linear dibasic side chain. Many of these chloroquine analogues have submicromolar antimalarial activity versus HB3 (chloroquine sensitive) and Dd2 (chloroquine resistant strain of Plasmodium falciparum) and low resistance indices were obtained in most cases. Importantly, compounds 11–15 and 24 proved to be more potent against Dd2 than chloroquine. Branching of the side chain structure proved detrimental to the activity against the CQR strain.     

Inhibition of malaria parasite growth by quinomycin A and its derivatives through DNA-intercalating activity

Quinomycin A and its derivatives were identified as potent antimalarial (Plasmodium falciparum) agents in a screen of the RIKEN NPDepo chemical library. IC₅₀ values of quinomycin A and UK-63,598 were approximately 100 times lower than that of the antimalarial drug chloroquine. This activity was mitigated by the addition of plasmid DNA, suggesting that these compounds act against parasites by intercalating into their DNA.     

Synthesis and structure–activity relationships of cassiarin A as potential antimalarials with vasorelaxant activity

Cassiarin A 1, a tricyclic alkaloid, isolated from the leaves of Cassia siamea (Leguminosae), shows powerful antimalarial activity against Plasmodium falciparum in vitro as well as P. berghei in vivo, which may be valuable leads for novel antimalarials. Interactions of parasitized red blood cells (pRBCs) with endothelium in aorta are especially important in the processes contribute to the pathogenesis of severe malaria. Nitric oxide (NO) reduces endothelial expression of receptors/adhesion molecules used by pRBC to adhere to vascular endothelium, and reduces cytoadherence of pRBC to vascular endothelium. Cassiarin A 1 showed vasorelaxation activity against rat aortic ring, which may be related with NO production. A series of a hydroxyl and a nitrogen-substituted derivatives and a dehydroxy derivative of 1 have been synthesized as having potent antimalarials against P. falciparum with vasodilator activity, which may reduce cytoadherence of pRBC to vascular endothelium. Cassiarin A 1 exhibited a potent antimalarial activity and a high selectivity index in vitro, suggesting that the presence of a hydroxyl and a nitrogen atom without any substituents may be important to show antimalarial activity. Relative to cassiarin A, a methoxy derivative showed more potent vasorelaxant activity, although it did not show improvement for inhibition of P. falciparum in vitro. These cassiarin derivatives may be promising candidates as antimalarials with different mode of actions.     

Structure–activity relationship studies of manzamine A: Amidation of positions 6 and 8 of the β-carboline moiety

Twenty manzamine amides were synthesized and evaluated for in vitro antimalarial and antimicrobial activities. The amides of manzamine A (1) showed significantly reduced cytotoxicity against Vero cells, although were less active than 1. The structure–activity analysis showed that linear, short alkyl groups adjacent to the amide carbonyl at position 8 are favored for antimalarial activity, while bulky and cyclic groups at position 6 provided the most active amides. Most of the amides showed potent activity against Mycobacterium intracellulare. The antimicrobial activity profile for position 8 series was similar to that for antimalarial activity profile, in which linear, slightly short alkyl groups adjacent to the amide carbonyl showed improved activity. Two amides 14 and 21, which showed potent antimalarial activity in vitro against Plasmodium falciparum were further evaluated in vivo in Plasmodium berghei infected mice. Oral administration of 14 and 21 at the dose of 30 mg/kg (once daily for three days) caused parasitemia suppression of 24% and 62%, respectively, with no apparent toxicity.     

Synthesis of new pyridothienopyrimidinone and pyridothienotriazolopyrimidine derivatives as pim-1 inhibitors

Three series of 2-arylpyridothieno[3,2-d]pyrimidin-4-ones 3a–j, pyridothienotriazolopyrimidines 6–8 and 4-imino-pyridothieno[3,2-d]pyrimidines 9a,b were prepared to improve the pim-1 inhibitory activity of the previously reported 2-arylpyridothieno[3,2-d]pyrimidin-4-ones. All the test compounds showed highly potent pim-1 inhibition with IC₅₀ in the range of 0.06–1.76?µM. No significant difference was detected between the pim-1 inhibitory activity of the 4-pyrimidinone and the 4-imino (=NH) or the cyclised triazolopyrimidine derivatives. The most active compounds were tested for their cytotoxic activity on MCF7 and HCT116 and showed potent activity on both the cell lines.     

Role of Molecular Electronic Properties of Some Novel Antimalarial Cyclic Peroxy Ketals in Relation to Potency and Potential Toxicity

Calculated molecular electronicproperties of 20 recently reported cyclic peroxy ketals have been rationalized with their in vitro antimalarial activity with the overall goal to guide the design for safer and effective peroxide-containing antimalarial agents. Stereoelectronicproperties were calculated on the optimized geometry of each compound using the ab initio 3-21G* quantum chemical basis set. Potency appears to be related to electronic properties rather than structural properties such as bond lengths and bond angles though an aliphatic cyclic ring seems to be a structural requirement for potent activity. Electronic properties such as differences in molecular polarity, in electrostatic potential profiles about the peroxide bond and the aromatic ring, in peroxide bond strength, and in the LUMO orbital energy of the molecules are all associated with potency. The three-dimensionalisopotential profile beyondthe van der Waals surface at –10 kcal/mol for the more potent analogs has a distinct large negative potential region by the aromatic ring extending to the methoxy moiety, suggesting a site for initial recognition interaction with the receptor away from the peroxide bond. The HOMO and LUMO isodensity surfaces for all molecules are located on the aromatic ring. The peroxide bond strength of the compounds is around 100 kcal/mol greater than the peroxide-containing clinically used antimalarial artemisinin compounds. In addition, density of the peroxy ketals also appears related to potent activity. The above features of the cyclic peroxy ketals are consistent with these compounds being less potent than the artemisinin compounds, but at the same time are less likely to be as neurotoxic as the artemisinins.     

Synthesis and characterization of biologically significant 5,5′-(1,4-phenylene)bis(1-N-alkoxyphthalimido-3-aryl-2-pyrazoline) derivatives

A facile synthesis of 5,5′-(1,4-phenylene)bis(3-aryl-2-pyrazolines) 4a-g has been achieved by the cyclo-addition reaction of hydrazine hydrate with bis-substituted chalcones 3a-g, which in turn were prepared by the Clasien-Schmidt condensation of p-substituted acetophenones 1a-g with terephthaldehyde. Condensation of 4a-g with ω-bromoalkoxyphthalimides 5a-b afforded the titled compounds 6a-n, some of which exhibited significant antimalarial as well as antimicrobial activity.     

Urease inhibitors from Hypericum oblongifolium WALL.

The bioassay-guided fractionation of H. oblongifolium has led to the isolation of potent urease inhibitors 1–3. The structures were elucidated by NMR and mass spectroscopic techniques. Compound 2 showed a potent enzyme inhibition activity (IC₅₀ 20.96?±?0.93), which is comparatively higher than that for the standard thiourea (IC₅₀ 21.01?±?0.51 μM). Compounds 1 and 3 also showed a significant activity, with IC₅₀ 37.95?±?1.93 and 138.43?±?1.23 μM, respectively. The sub crude fractions (F1, F2, F3, and F4) were tested in vitro for their urease inhibition activity. Fractions F2 and F4 showed significant activity with IC₅₀ 140.37?±?1.93 and 167.43?±?3.03 μM, respectively.     

Addressing the malaria drug resistance challenge using flow cytometry to discover new antimalarials

A new flow cytometry method that uses an optimized DNA and RNA staining strategy to monitor the growth and development of the Plasmodium falciparum strain W2mef has been used in a pilot study and has identified Bay 43-9006 1, SU 11274 2, and TMC 125 5 as compounds that exhibit potent (<1 μM) overall and ring stage in vitro antimalarial activity.     

Synthesis of new pyridothienopyrimidinone derivatives as Pim-1 inhibitors

Four series of pyridothienopyrimidin-4-one derivatives were designed and prepared to improve the pim-1 inhibitory activity of the previously reported thieno[2,3-b]pyridines. Significant improvement in the pim-1 inhibition and cytotoxic activity was achieved using structure rigidification strategy via ring closure. Six compounds (6c, 7a, 7c, 7d, 8b and 9) showed highly potent pim-1 inhibitory activity with IC₅₀ of 4.62, 1.18, 1.38, 1.97, 8.83 and 4.18?μM, respectively. Four other compounds (6b, 6d, 7b and 8a) showed moderate pim-1 inhibition. The most active compounds were tested for their cytotoxic activity on three cell lines [MCF7, HCT116 and PC3]. Compounds 7a [the 2-(2-chlorophenyl)-2,3-dihydro derivative] and 7d [the 2-(2-(trifluoromethyl)-phenyl)-2,3-dihydro derivative] displayed the most potent cytotoxic effect on the three cell lines tested consistent with their highest estimated pim-1 IC₅₀ values.     

3-Benzylidene-4-chromanones: a novel cluster of anti-tubercular agents

Abstract

In a quest for developing novel anti-tubercular agents, a series of 3-benzylidene-4-chromanones 1a–l were evaluated for growth inhibition of Mycobacterium tuberculosis H₃₇Rv. Three promising compounds 1d, g, j emerged as the lead compounds with the IC₅₀ and IC₉₀ values of less than 1?µg/mL. Evaluation of the potent compounds 1d, g, j and k against Vero monkey kidney cells revealed that these compounds are far more toxic to M. tuberculosis than to Vero cells. Structure–activity relationships demonstrated that 3-benzylidene-4-chromanones are more potent against M. tuberculosis than the related 2-benzylidene cycloalkanones and the meta substituted chromanone derivatives are more active than their ortho- and para-counterparts. Some guidelines for amplifying the project are presented.     

Synthesis and potential antitumor activity of 7-(4-substituted piperazin-1-yl)-4-oxoquinolines based on ciprofloxacin and norfloxacin scaffolds: in silico studies

The potential antitumor activities of a series of 7-(4-substituted piperazin-1-yl)fluoroquinolone derivatives (1–14a,b) using ciprofloxacin and norfloxacin as scaffolds are described. These compounds exhibit potent and broad spectrum antitumor activities using 60 human cell lines in addition to the inherent antibacterial activity. Compounds 1a, 2a, 3b, 6b and 7a were found to be the most potent, while 2b, 5b, and 6a were found to have an average activity. The results of this study demonstrated that compounds 1a, 2a, 3b, 6b and 7a (mean GI₅₀; 2.63–3.09?µM) are nearly 7-fold more potent compared with the positive control 5-fluorouracil (mean GI₅₀; 22.60?µM). More interestingly, compounds 1a, 2a, 3b, 6b and 7a have an almost antitumor activity similar to gefitinib (mean GI₅₀; 3.24?µM) and are nearly 2-fold more potent compared to erlotinib (mean GI₅₀; 7.29?µM). In silico study and ADME-Tox prediction methodology were used to study the antitumor activity of the most active compounds and to identify the structural features required for antitumor activity.     

Anticancer and immunomodulatory activities of novel 1,8-naphthyridine derivatives

A number of 1,8-naphthyridine derivatives (22–62) have been synthesized and screened for their in vitro cytotoxicity against eight tumors and two non-tumor cell lines. Halogen substituted 1,8-naphthyridine-3-caboxamide derivatives showed potent activity with compound 47 having IC₅₀ of 0.41 and 0.77 μM on MIAPaCa and K-562 cancer cell lines, respectively while, compound 36 had IC₅₀ of 1.19 μM on PA-1 cancer cell line. However, one of the unsubstituted 1,8-naphthyridine-C-3’-heteroaryl derivative 29 showed potent cytotoxicity with IC₅₀ of 0.41 and 1.4 μM on PA-1 and SW620 cancer cell lines, respectively. These compounds were also evaluated for anti-inflammatory activity as suggested by downregulation of proinflammaotory cytokines.     

Isariotins G–J from cultures of the Lepidoptera pathogenic fungus Isaria tenuipes

Four new alkaloids isariotins G–J (1–4), together with the known isariotins, were isolated from cultures of the Lepidoptera pathogenic fungus Isaria tenuipes. The structures were elucidated on the basis of NMR spectroscopic and mass spectrometry data. Compounds 1–4 exhibited antimalarial and cytotoxic activities.