Enoyl reductase: One target, Two major Global Threats

Tuberculosis and Malaria are two major global threats; both account for 5 million deaths annually (mostly in developing countries). Despite the worldwide ravages of Tuberculosis and Malaria, chemotherapeutic regimens against these two diseases have remained largely unchanged. There is an urgent need to develop novel, effective, and affordable drugs to treat both diseases because the resistance has developed or is developing to existing therapy. Scientists around the world are seeking new ways to combat the two opportunistic pathogens.

Mycobacterium tuberculosis and Plasmodium Falciparum are causative agents of tuberculosis and malaria, respectively. Both organisms share enzymatic components of the type II fatty acid biosynthetic pathway (FAS-II). Enoyl acyl carrier protein reductase (ENR) is one of the key type II enzymes, has been repeatedly validated as an effective antimicrobial target (e.g., INH, diazoborines, triclosan, and thiolactomycin).

Triclosan, the ENR inhibitor, showed excellent activity against both organisms. Targeting ENR  with a new class of compounds may yield new drugs against these devastating pathogens.

Toxicophores Simplified

Toxicophore is a portion of a chemical structure (molecular functionalities) responsible for the toxic properties of a pharmacologically activity compound. Medicinal chemists study toxicophores to predict and replace the potential reactive moieties in the early drug development process to avoid the drug candidate's later-stage failure. A simplified version of the toxicophores is attached here.

Retropharmacology: From Drug to lead

Drug discovery is a lengthy, high-risk, and costly endeavor; many strategies are available to accelerate the development process to provide high-quality drug candidates. The diminished interest in Natural products drug discovery as the industry embraced promising and exciting new technologies, particularly combinatorial chemistry. However, these new technologies promise to fill the drug development pipeline with small-molecule candidates is unfulfilled. Learning from the past with the appropriate strategy for the future is essential to make a significant difference.

Valerian has been used as a medicinal herb science at least the time of ancient Greece and Rome as a sedative, migraine treatment, pain reliever, insomnia, and other disorders as an alternative to benzodiazepine drugs.

Valerenic acid, a significant constituent of common valerian, is a potent modulator of  GABA-A receptors. In order to develop a broader understanding of structural requirements for GABA-A modulatory activity of valerenic acid. Kopp et al. (chem med chem) synthesized several analogs and found that some of the derivatives such as tetrazole (pic) are proved to be the most potent allosteric potentiators of GABA-induced ion currents, and its activity exceeds the activity of valerenic acid and Diazepam.

This reverse pharmacology approach, relates to reversing the routine ‘laboratory-to-clinic’ progress to ‘clinics-to-laboratories’ (inspired by traditional medicine), can offer a smart strategy for new drug candidates.

N-Methylation and Oral Bioavailability.

Inspired by the excellent pharmacokinetic profile of transplantation drug, cyclosporine A (a natural, N-methylated cyclic peptide), which can be administered orally, Kessler reported that multiple N-methylation is a promising way to rationally improve key pharmacokinetic characteristics in peptides.

N-methyl scan of the cyclopeptidic somatostatin analog cyclo(-PFwKTF-), known as the Veber−Hirschmann peptide, improves not only oral bioavailability but also receptor selectivity.

Another interesting question is to what extent might the N methylation contribute to the bioavailability (the ADMET profile) in the amide of small molecules rather than peptides? For example, Tubulin-binding taxanes such as paclitaxel and docetaxel are important cancer chemotherapeutic agents. However, these drugs suffer from limitations such as poor aqueous solubility and oral bioavailability, emerging drug resistance, and the lack of blood-brain barrier permeability.

N-methyltaxol C (methylation of the C3′ amide of taxol C), a potential impurity in clinically used taxanes, showed improved bioavailability. This result demonstrates the utility of N-methylation to improve key pharmacokinetic characteristics in amides.

The making of hERG free molecules (The Role of Fluorine)

The unwanted hERG affinity could be removed by moderating 

1) basicity (control pka),

2) lipophilicity of the compound, and 

3) steric environment of the central nitrogen 

A paper in BMCL from Pfizer reported the pka, lipophilicity, independent optimization of hERG affinity for the CCR5 antagonist ‘Maraviroc’. The steric demand and the dipole generated by the difluoro moiety of 4 4’difluoro cyclohexyl group in maraviroc are clearly not tolerated within the hERG channel.

 

Overcoming hERG affinity in kinesin spindle protein inhibitor MK-0731 for the treatment of Taxane Refractory Cancer was achieved by making axial fluorine in the piperidine ring.

The rule of three and ADMET

Paul Gleeson from GSK has come up with a set of rules of thumb for the three crucial property of drug namely molecular weight, log P, and ionization state (which medicinal chemist comfortable and familiar with) that influence their ADMET behavior Such as Solubility, Permeability, Bioavailability, Volume of distribution, Plasma protein binding, CNS penetration, Brain tissue binding, P-gp efflux, hERG inhibition, and Cytochrome-P450. This study is vital for the pharmaceutical industry because up to 40 % of promising candidates fail in clinical trials due to unfavorable pharmacological properties in drug development. His study re-emphasizes the need to focus on a lower molecular weight and log P area of physicochemical property space to obtain improved ADMET parameters.

Fluorine in Drug Discovery

The importance of Fluorine in medicinal chemistry is well recognized. Indeed, an increasing number of drugs on the market contain Fluorine, the presence which often is of major importance to activity. A recent review article (Chem. Soc. Rev., 2008, 37, 320) by Sophie Purser describes the role of Fluorine in medicinal chemistry.

Replacement of hydrogen with Fluorine (F) in a pharmacologically active molecule can profoundly change the conformational preference due to its size difference and stereoelectronic effects.

1) F can enhance binding efficacy and selectivity in pharmaceuticals.

2) F substituents on ligands prefer to orient toward electropositive regions of receptor sites.

3) Distinct fluorofilic environment in proteins includes the ubiquitous peptide bonds, which undergo multipolar C-F…H-N, C-F..C=O and C-F..H-C interaction.

Systematic fluorine scans of ligands is a promising strategy during the lead optimization stage of drug discovery. Fluorine substitution enhances physicochemical and adsorption, distribution, metabolism, and excretion properties and strengthens protein-ligand binding interaction.

The effects of Fluorine substitution expands, further applications in drug discovery will emerge. 

Modern fluorine organic chemistry has dramatically widened the synthetic repertoire for the specific introduction of Fluorine in an organic molecule.

Racemic Switch

A racemic switch or chiral switch is the redevelopment in the single-enantiomer form of a drug that was first approved as a racemates (racemic mixture). Sometimes, the pharmaceutical activity of a racemic mixture is present only in one enantiomer, and the other is inactive, or the other enantiomer has an undesired activity from the first.

Omeprazole

For exmaple, Omeprazole is an Antiulcer drug (AstraZeneca) marketed in the U.S. as a racemic drug in 1995. It s a racemic mixture of R-omeprazole and S-omeprazole. Since its patent ran out in 2002 and the pharmacological activity lies in (S)-enantiomer, the company has patented now (S)-omeprazole named as esomeprazole.