Kelly Chibale

Novel web-based tools combining chemistry informatics, biology and social networks for drug discovery

A convergence of different commercial and publicly accessible chemical informatics, databases and social networking tools is positioned to change the way that research collaborations are initiated, maintained and expanded, particularly in the realm of neglected diseases. A community-based platform that combines traditional drug discovery informatics with Web2.0 features in secure groups is believed to be the key to facilitating richer, instantaneous collaborations involving sensitive drug discovery data and intellectual property. Heterogeneous chemical and biological data from low-throughput or high-throughput experiments are archived, mined and then selectively shared either just securely between specifically designated colleagues or openly on the Internet in standardized formats. We will illustrate several case studies for anti-malarial research enabled by this platform, which we suggest could be easily expanded more broadly for pharmaceutical research in general.

The State of the Art in Anti-Malarial Drug Discovery and Development

Malaria is one of the most prevalent and devastating infectious diseases of our time. Yet, unfortunately, apart from artemisinin combination therapies there are relatively few effective treatments for Plasmodium falciparum and only one treatment for the radical cure of Plasmodium vivax. Novel classes of antimalarial medicines are urgently needed given the long-term inevitability of resistance to current therapies and the need for drugs that are well tolerated by all. This review summarises the antimalarials developed and registered thus far, as well as describing some of the new small molecule therapy approaches being developed as a contribution towards the malaria eradication agenda.

Design, synthesis and in vitro antimalarial evaluation of triazole-linked chalcone and dienone hybrid compounds

A targeted series of chalcone and dienone hybrid compounds containing aminoquinoline and nucleoside templates was synthesized and evaluated for in vitro antimalarial activity. The Cu(I)-catalyzed cycloaddition of azides and terminal alkynes was applied as the hybridization strategy. Several chalcone-chloroquinoline hybrid compounds were found to be notably active, with compound 8b the most active, exhibiting submicromolar IC(50) values against the D10, Dd2 and W2 strains of Plasmodium falciparum.

Synthesis, antimalarial and antitubercular activity of acetylenic chalcones

A series of acetylenic chalcones were evaluated for antimalarial and antitubercular activity. The antimalarial data for this series suggests that growth inhibition of the W2 strain of Plasmodium falciparum can be imparted by the introduction of a methoxy group ortho to the acetylenic group. Most compounds were more active against non-replicating than replicating cultures of Mycobacterium tuberculosis H(37)Rv, an unusual pattern with respect to existing anti-TB agents.

3,5-Diaryl-2-aminopyridines as a Novel Class of Orally Active Antimalarials Demonstrating Single Dose Cure in Mice and Clinical Candidate Potential

A novel class of orally active antimalarial 3,5-diaryl-2-aminopyridines has been identified from phenotypic whole cell high-throughput screening of a commercially available SoftFocus kinase library. The compounds were evaluated in vitro for their antiplasmodial activity against K1 (chloroquine and drug-resistant strain) and NF54 (chloroquine-susceptible strain) as well as for their cytotoxicity. Synthesis and structure-activity studies identified a number of promising compounds with selective antiplasmodial activity. One of these frontrunner compounds, 15, was equipotent across the two strains (K1 = 25.0 nM, NF54 = 28.0 nM) and superior to chloroquine in the K1 strain (chloroquine IC(50) K1 = 194.0 nM). Compound 15 completely cured Plasmodium berghei-infected mice with a single oral dose of 30 mg/kg. Dose-response studies generated ED(50) and ED(90) values of 0.83 and 1.74 mg/kg for 15 in the standard four-dose Peters test. Pharmacokinetic studies in the rat indicated that this compound has good oral bioavailability (51% at 20 mg/kg) and a reasonable half-life (t(1/2) ∼ 7-8 h).

Synthetic medicinal chemistry of selected antimalarial natural products

Natural products remain a rich source of novel molecular scaffolds for novel antimalarial agents in the fight against malaria. This has been well demonstrated in the case of quinine and artemisinin both of which have served as templates for the development of structurally simpler analogues that either served or continue to serve as effective antimalarials. This review will expound on these two natural products as well as other selected natural products that have served either as antimalarial agents or as potential lead compounds in the development of antimalarial drugs.

Enone― and Chalcone―Chloroquinoline Hybrid Analogues: In Silico Guided Design, Synthesis, Antiplasmodial Activity, in Vitro Metabolism, and Mechanistic Studies

Analogues of the previously reported antimalarial hybrid compounds 8b and 12 were proposed with the aim of identifying compounds with improved solubility and retained antimalarial potency. In silico characterization predicted improved solubilities of the analogues, particularly at low pH; they retained acceptable predicted permeability properties but were predicted to be susceptible to hepatic metabolism. These analogues were synthesized and found to exhibit notable in vitro antimalarial activity. Compounds 25 and 27 were the most active of the analogues. In vitro metabolism studies indicated susceptibility of the analogues to hepatic metabolism. There was also evidence of primary glucuronidation for analogues 24-27. Presumed cis-trans isomerism of 12, 22, and 23 under in vitro metabolism assay conditions was also observed, with differences in the nature and rates of metabolism observed between isomers. Biochemical studies strongly suggested that inhibition of hemozoin formation is the primary mechanism of action of these analogues.

Drug repositioning in the treatment of malaria and TB

The emergence and spread of drug resistance in the malaria parasite Plasmodium falciparum as well as multi- and extremely drug-resistant forms of Mycobacterium tuberculosis, the causative agent of TB, could hamper the control of these diseases. For instance, there are indications that the malaria parasite is becoming resistant to artemisinin derivatives, drugs that form the backbone of antimalarial combination therapy. Likewise, Mycobacterium tuberculosis strains that are multidrug-resistant or extremely drug-resistant to first- and second-line drugs have been associated with increased mortality. Thus, more than ever, new antimalarials and anti-TB drugs are needed. One of the strategies to discover new drugs is to reposition or repurpose existing drugs, thus reducing the cost and time of drug development. In this review, we discuss how this concept has been used in the past to discover antimalarial and anti-TB drugs, and summarize strategies that can lead to the discovery and development of new drugs.

New amine and urea analogs of ferrochloroquine: synthesis, antimalarial activity in vitro and electrochemical studies

Amine and urea analogs of ferrochloroquine with varying methylene spacer lengths were synthesised, studied by cyclic voltammetry and evaluated in vitro against a sensitive (D10) and resistant (K1) strain of Plasmodium falciparum. Most analogs were found to be more active than chloroquine in both strains. In D10 ureas were more active than amines and antimalarial activity in this strain correlated well with the length of the methylene spacer and redox potentials. The length of the methylene spacer was a major determinant of antimalarial activity in K1.

Facile transformation of Biginelli pyrimidin-2(1H)-ones to pyrimidines. In vitro evaluation as inhibitors of Mycobacterium tuberculosis and modulators of cytostatic activity

A series of pyrimidine derivatives bearing amine substituents at C-2 position were obtained from Biginelli 3,4-dihydropyrimidin-2(1H)-ones and the effect of structural variation on anti-TB activity against Mycobacterium tuberculosis H37Rv strain and antiviral activity in a series of cell cultures was evaluated. While the compounds were found to possess structure dependent cytostatic activity, these were not found to be efficient inhibitors of M. tuberculosis nor did they inhibit a broad variety of DNA or RNA viruses in cell culture.