Identification of selective tubulin inhibitors as potential anti-trypanosomal agents

The potency of a series of sulfonamide tubulin inhibitors against the growth of Trypanosoma brucei (T. brucei), as well as human cancer and primary fibroblast cells were evaluated with the aim of determining whether compounds that selectively inhibit parasite proliferation could be identified. Several compounds showed excellent selectivity against T. brucei growth, and have the potential to be used for the treatment of Human African trypanosomiasis. A T. brucei tubulin protein homology model was built based on the crystal structure of the bovine tubulin. The colchicine-binding domain, which is also the binding site of the tested sulfonamide tubulin inhibitors, showed clear differences between the tubulin structures and presumably explained the selectivity of the compounds.     

SAR studies on azasterols as potential anti-trypanosomal and anti-leishmanial agents

There is an urgent need for the development of new drugs for the treatment of neglected tropical diseases such as human African trypanosomiasis, Chagas disease and leishmaniasis. Azasterols, have been shown to have activity against the parasites which cause these diseases. In this paper we report synthesis of new azasterols and subsequent analysis of the SAR. The chemistry focused on variations in the ester at the 3β-position of the sterol and the position of the nitrogen in the side chain. The data allowed us to derive preliminary pharmacophore models for the activity of the azasterols against the parasites which cause these diseases.     

Squalamine analogues as potential anti-trypanosomal and anti-leishmanial compounds

This paper concerns the synthesis of various simplified analogues of the novel anti-microbial agent, squalamine. The compounds were then investigated for activity against Trypanosoma brucei, the causative agent of African trypanosomiasis, Trypanosoma cruzi, the causative agent of Chagas disease and Leishmania donovani, the causative agent of visceral leishmaniasis. Several compounds showed in vitro activity, especially against T. brucei and L. donovani. However, one compound showed poor in vivo activity.     

Lead optimization of selective tubulin inhibitors as anti-trypanosomal agents

Previously synthesized tubulin inhibitors showed promising in vitro selectivity and activity against Human African Trypanosomiasis. Current aim is to improve the ligand efficiency and reduce overall hydrophobicity of the compounds, by lead optimization. Via combinatorial chemistry, 60 new analogs were synthesized. For biological assay Trypanosoma brucei brucei Lister 427 cell line were used as the parasite model and for the host model human embryonic kidney cell line HEK-293 and mouse macrophage cell line RAW 264.7 were used to test efficacy. Of the newly synthesized compounds 5, 39, 40, and 57 exhibited IC₅₀s below 5?µM inhibiting the growth of trypanosome cells and not harming the mammalian cells at equipotent concentration. Comparably, the newly synthesized compounds have a reduced amount of aromatic moieties resulting in a decrease in molecular weight. Due to importance of tubulin polymerization during protozoan life cycle its activity was assessed by western blot analyses. Our results indicated that compound 5 had a profound effect on tubulin function. A detailed structure activity relationship (SAR) was summarized that will be used to guide future lead optimization.     

Synthesis and exploration of novel curcumin analogues as anti-malarial agents

Curcumin, a major yellow pigment and active component of turmeric, has been shown to possess anti-inflammatory and anti-cancer activities. Recent studies have indicated that curcumin inhibits chloroquine-sensitive (CQ-S) and chloroquine-resistant (CQ-R) Plasmodium falciparum growth in culture with an IC(50) of approximately 3.25 microM (MIC=13.2 microM) and IC(50) 4.21 microM (MIC=14.4 microM), respectively. In order to expand their potential as anti-malarials a series of novel curcumin derivatives were synthesized and evaluated for their ability to inhibit P. falciparum growth in culture. Several curcumin analogues examined show more effective inhibition of P. falciparum growth than curcumin. The most potent curcumin compounds 3, 6, and 11 were inhibitory for CQ-S P. falciparum at IC(50) of 0.48, 0.87, 0.92 microM and CQ-R P. falciparum at IC(50) of 0.45 microM, 0.89, 0.75 microM, respectively. Pyrazole analogue of curcumin (3) exhibited sevenfold higher anti-malarial potency against CQ-S and ninefold higher anti-malarial potency against CQ-R. Curcumin analogues described here represent a novel class of highly selective P. falciparum inhibitors and promising candidates for the design of novel anti-malarial agents.     

Novel and potent anti-malarial agents

Readily accessible, novel, and potent anti-malarial compounds have been developed. Optimization of the initial lead structure resulted in derivatives with IC50 values from 7 to 35 nM against chloroquine-sensitive and 70-350 nM against chloroquine-resistant strains of Plasmodium falciparum.     

Synthesis and evaluation of phenoxyoxazaphospholidine,phenoxyoxazaphosphinane, and benzodioxaphosphininamine sulfides and related compounds as potential anti-malarial agents

A series of phenoxyoxazaphospholidine, phenoxyoxazaphosphinane and benzodioxaphosphininamine sulfides and related cyclic organophosphorus compounds based on the lead anti-tubulin herbicides amiprophos methyl and butamifos were synthesised and evaluated for anti-malarial activity. Of these compounds, while none of the phenoxyoxazaphospholidines, phenoxyoxazaphosphinanes or benzodioxaphosphininamine sulphides were more potent than APM, phosphorothioamidate 30, a dual compound also bearing an aminoquinoline motif, showed promising activity against Plasmodium falciparum (IC₅₀ 0.038 μM) and warrants further study.     

Synthesis and biological screening of some pyridine derivatives as anti-malarial agents

Two series of pyridine derivatives were synthesised and evaluated for their in vivo anti-malarial activity against Plasmodium berghei. The anti-malarial activity was determined in vivo by applying 4-day standard suppressive test using chloroquine (CQ)-sensitive P. berghei ANKA strain-infected mice. Compounds 2a, 2g and 2h showed inhibition of the parasite multiplication by 90, 91 and 80%, respectively, at a dose level of 50 μmol/kg. Moreover, The most active compounds (2a, 2g and 2h) were tested in vitro against CQ-resistant Plasmodium falciparum RKL9 strains where compound 2g showed promising activity with IC(50)?=?0.0402 μM. The compounds were non-toxic at 300 and 100?mg/kg through the oral and parenteral routes, respectively. The docking pose of the most active compounds (2a, 2g and 2h) in the active site of dihydrofolate reductase enzyme revealed several hydrogen and hydrophobic interactions that contribute to the observed anti-malarial activities.     

Identification of plasmepsin inhibitors as selective anti-malarial agents using ligand based drug design

We describe the application of ligand based virtual screening technologies towards the discovery of novel plasmepsin (PM) inhibitors, a family of malarial parasitic aspartyl proteases. Pharmacophore queries were used to screen vendor libraries in search of active and selective compounds. The virtual hits were biologically assessed for activity and selectivity using whole cell Plasmodium falciparum parasites and on target in PM II, PM IV and the closely related human homologue, Cathepsin D assays. Here we report the virtual screening highlights, structures of the hits and their demonstrated biological activity.     

Analogues of 4,5-bis(3,5-dichlorophenyl)-2-trifluoromethyl-1H-imidazole as potential antibacterial agents

A preliminary exploration of analogues of 4,5-bis(3,5-dichlorophenyl)-2-trifluoromethyl-1H-imidazole, 1, as novel antibacterial agents was carried out to determine the basic features of the structure responsible for the observed biological activity. The presence of two aryl rings, the imidazole NH and either a good electron withdrawing group or an aldehyde or amino group at C-2 were required for good levels of activity against methicillin resistant Staphylococcus aureus (MRSA).     

Microtubule inhibitors as potential antimalarial agents

The Steering Committee on Drugs for Malaria (CHEMAL) of the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) has identified tubulin as a potential drug target, but one that is not yet ;validated'. Several inhibitors of tubulins, the principal proteins of microtubules, are potent inhibitors of the development and multiplication of malarial parasites in culture and in vivo. However, most of these compounds are also inhibitors of mammalian cell proliferation. Here, Angus Bell reviews the structure and properties of microtubules, their roles in Plasmodium cells, and the effects of various microtubule inhibitors on the parasite. He argues that microtubule inhibitors are not equally toxic to all proliferating cells but, by virtue of differential tubulin binding, show selective toxicity that might allow their use as antimalarial drugs.     

Pregnenolone derivatives as potential anticancer agents

Pregnenolone (1) was used as a template to develop new anticancer compounds. Ring-D modification of 1 resulted in the synthesis of benzylidenes 2-17, pyrazolines 18-76, pyrazoles 85-91, hydrazones 77-84, and oximes 92-107 derivatives. The structure of compound 107 was also deduced through single crystal X-ray diffraction studies. The inclusion of furanyl and pyridyl rings to pregnenolone skeleton increases the cytotoxicity of all compounds significantly. Among benzylidene derivatives, only heterocyclic enone 8 (IC₅₀ = 0.74 μM/mL against HepG2), and 17 (IC₅₀ = 4.49 μM/mL against HepG2, IC₅₀ = 5.01 μM/mL against MDA-MB-230 cancer cell line) exhibited a significant activity. The cytotoxicity data of pyrazoline derivatives 18-76 revealed that only furanyl bearing pyrazolines 40, 42-44, 48, and 49 exhibited significant activities. While all (O-carboxymethyl) oximes, hydazones, and pyrazoles derivatives of pregnenolone did not show any significant activity against both the cell lines. Thus the furanyl bearing enone 8 (IC₅₀ = 0.74 μM/mL against HepG2), and its pyrazoline derivative 48 (IC₅₀ = 0.91 μM/mL against MDA-MB-230 cancer cell lines) were identified as the most active compounds in all derivatives of pregnenolone.     

Quinol derivatives as potential trypanocidal agents

Quinols have been developed as a class of potential anti-cancer compounds. They are thought to act as double Michael acceptors, forming two covalent bonds to their target protein(s). Quinols have also been shown to have activity against the parasite Trypanosoma brucei, the causative organism of human African trypanosomiasis, but they demonstrated little selectivity over mammalian MRC5 cells in a counter-screen. In this paper, we report screening of further examples of quinols against T. brucei. We were able to derive an SAR, but the compounds demonstrated little selectivity over MRC5 cells. In an approach to increase selectivity, we attached melamine and benzamidine motifs to the quinols, because these moieties are known to be selectively concentrated in the parasite by transporter proteins. In general these transporter motif-containing analogues showed increased selectivity; however they also showed reduced levels of potency against T. brucei.     

GlycineB antagonists as potential therapeutic agents

Summary It is not clear what therapeutic application is most likely for agents blocking glycine site of the NMDA receptors (glycine_B). Majority of the studies to date used either glycine_B antagonists with doubtful brain penetration or partial agonists. Following systemic administration to rats of our newly developed glycme_B antagonists (MRZ 2/570; 2/571 and 2/576) and L-701,324 (MSD) as a reference agent the following behavioural effects were observed: weak (if any) antiparkinsonian-like effects, lack of anxiolytic activity, inhibition of physical and motivational aspects of morphine dependence and neuroprotective activity in global ischaemia. The side effects include: sedation, ataxia, and myorelaxation. We detected neither vacuolisation in the cingulate cortex nor impairment of pre-pulse inhibition indicating lack of psychotomimetic potential.     

DNA aptamers as potential anti-HIV agents

Guanine (G)-rich DNA sequences can adopt stable G-quadruplex structures by G-tetrad hydrogen-bonding and hydrophobic stacking. Recently, it has been shown that a DNA sequence forms an aptamer (termed 93del) and adopts a novel dimeric quadruplex folding topology in K+ solution. This aptamer exhibits anti-HIV1 integrase activity in the nanomolar range in vitro. A docking-based model of the 93del-integrase complex positions the DNA aptamer within a channel of the tetrameric integrase. This mutual fitting blocks several catalytic amino acid residues that are essential for integrase function, and accounts for the anti-HIV1 activity of the 93del aptamer.     

Thiazolyl-pyrazole derivatives as potential antimycobacterial agents

Mycobacterium tuberculosis (Mtb) is an obligate aerobe that is capable of long-term persistence under conditions of low oxygen tension. A series of thiazolyl-pyrazole derivatives (6a–f, 7a–f, 8c, 8e) were screened for antimycobacterial activity against dormant M. tuberculosis H37Ra (D-MTB) and M. bovis BCG (D-BCG). Nine thiazolyl-pyrazole analogs, 6c, 6e, 7a, 7b, 7c, 7e, 7f, 8c and 8e exhibited promissing minimum inhibitory concentration (MIC) values (0.20–28.25?µg/mL) against D-MTB and D-BCG strains of Mtb. Importantly, six compounds (7a, 7b, 7e, 7f, 8c and 8e) exhibited excellent antimycobacterial activity and low cytotoxicity at the maximum evaluated concentration of >250?µg/mL. Finally, the promising antimycobacterial activity and lower cytotoxicity profile suggested that, these compounds could be further subjected for optimization and development as a lead, which could have the potential to treat tuberculosis.     

Pyrrolomycins as potential anti-staphylococcal biofilms agents

With the goal of discovering new anti-infective agents active against microbial biofilms, this investigation focused on some natural pyrrolomycins, a family of halogenated pyrrole antibiotics. In this study the anti-staphylococcal biofilm activity of pyrrolomycins C, D, F1, F2a, F2b, F3 and of the synthesized related compounds I, II, III were investigated. The susceptibility of six staphylococcal biofilms was determined by methyltiazotetrazolium staining. Most of the compounds were active at concentrations of 1.5 μg ml^?1 with significant inhibition percentages. A few of the compounds were active at the lowest screening concentration of 0.045 μg ml^?1. The population log reduction of activity against the two best biofilm forming Staphylococcus aureus strains as determined by viable plate counts is also reported. In order to adequately assess the utility of these compounds, their toxicity against human cells was evaluated. It is concluded that pyrrolomycins and synthetic derivatives are promising compounds for developing novel effective chemical countermeasures against staphylococcal biofilms.     

Bacterial endotoxins as potential antitumor agents

Natural and modified preparations of lipopolysaccharides and lipopolysaccharide-protein complexes isolated from the S- and R-form of Shigella dysenteriae serovar 1 were found to markedly inhibit the initial growth of mouse solid tumors derived from Németh-Kellner lymphoma, Gardner 6C3HED lymphoma, an ill-defined syngeneic lymphoma of DBA mice (Skalsky lymphoma) and LP-2 plasmacytoma. The biopreparations were given intraperitoneally, most frequently at a dose range from 50 to 200 micrograms per mouse; significant inhibitory effects on tumor growth were evidenced even in mice bearing tumors weighing 113 to 507 mg.