Thursday, November 12, 2009

Kill the Bugs, Selectively

“Today, we have tuberculosis drugs you have to take for 9 months, why can’t we find one that work in three days”
- Bill Gates.

Tuberculosis (TB) is a chronic contagious disease caused by Mycobacterium tuberculosis (M.tb), is one of the leading caused of death worldwide. The WHO estimates about one-third of the world’s population is infected with M.tb, 10% of those infected will progress to active TB disease during their life time. The tuberculosis pandemic has been declared a global health emergency as the growing resistance of M.tb to Antibiotics coincides with the spread of risk factors such as HIV/AIDS and diabetes.

TB is a complex disease. The current TB drug regimen, a product of scientific advances of the 1960s, requires six to nine months of treatment for active, drug-susceptible TB. Unfortunately, many patients do not or cannot complete this treatment. Poor adherence and prescribing practices have led to the emergence of multi- and extensively drug resistant strains of TB (MDR-TB and XDR-TB) that increasingly defy current medicines and are spreading throughout many regions of the globe. The incidence of MRD- and XRD- TB demands renewed efforts in the development of novel class of fast acting anti TB chemotherapeutics.

Mycobacterium tuberculosis is one of the few bacterial species with a proteasome. A team of scientists led by researchers from Weill Cornell Medical College has found that some oxathiazolone compounds kill tuberculosis-causing bacteria by selectively inhibiting mycobacterial proteasomes without affecting human proteasomes. These compounds showing no apparent toxicity to mammalian cells. The oxathiazolone compounds are the first example of an anti-tubercular agent that inhibits protein breakdown. The ability of a brief exposure to oxathiazol-2-one compounds to inhibit M.tb proteasomes permanently makes it a potential target for anti-TB therapy.This findings may lead to drugs that destroy TB in dormant stage of lifecycle.

Saturday, September 5, 2009


A new strain of swine flu influenza a H1N1 virus is spreading around the globe. The WHO declared 2009 swine flu pandemic - First Phase 6 Influenza pendemic Since 1968.

(_)-Oseltamivir phosphate (Tamiflu), a neuraminidase inhibitor used in the treatment of both type A and type B human influenza,Currently the most effective drug for the treatment of Influenza. But the unmet supply of this drug demand urgent solutions. The manufacture of Tamiflu by Roche Company utilizing naturally occurring shikimic acid as the starting material. Getting stable quality of pure shikimic acid may be problematic.

The Tamiflu supply problem has piqued the attention of academic chemists. It is known that several labs have already reported new methods in making Tamiflu without shikimic acid. But it is very difficult to evaluate academic syntheses from the standpoint of potential as a manufacturing process because they have not been developed for the large-scale operation. Considering the amount of Tamiflu required worldwide, there is an urgent demand to improve the production process.

Here is the retro synthetic analyse for the short cut synthesis of Tamiflu. This synthesis initiated by oxa-Michael addition of alcohol to acrolin, which was reported by Zhang et al,

Saturday, July 18, 2009

Going Right-handed

Why we are made of only right-handed sugars? That’s long been one of the biggest puzzles in understanding how life began, and this origin of homochirality in sugars and amino acids have been intrigued researchers for decades. So for, convincing theory and experiment on the origin of homochirality are still lacking.

Armando Co´rdova and coworkers at Stockholm University, Sweden, used amino acid as catalyst for the formation of hexoses sugars with >99 ee. Hexose’s have been suggested as building blocks of ancient RNA. It may be an example of the theoretical basis for the evolution of homochirality of sugars(right handed configuration) in the prebiotic world.

Andrew Pohorille and Chenyu Wei at NASA Ames Research Center found that (JACS,2009) ribose permeates membranes an order of magnitude faster than its diastereomers. On this basis it was hypothesized that differences in membrane permeability to aldopentoses provide a basis for preferential delivery of ribose to primitive cells for subsequent selective incorporation into nucleotides and their polymers.

D ribose (right handed sugar) polynucleotide tend to form right handed helices, What is the neutral macroscopic cause that gave rise to preference of both right handed helical nucleic acids and proteins on earth?

Y J He et al suggested that a net natural chiral right-handed helical force field, produced by the Earth’s orbital chirality (EOC) could affect the stability of molecule helical enantiomers and make the right-handed helical enantiomers more stable than their left- handed enantiomers. So, terrestrial living systems must select both right-handed nucleic acids based on D-sugars and right-handed proteins based on L-amino acids.

This homochirality can be observed on the macroscopic scale, for example, in the helical chirality of snail shells (preferred right-handed) and the helical winding of some kind of plants.

May be full understanding of life and its evolution will never be possible. But this will not certainly stop scientist to seek the secret of the origin of life. Whitesides recently expressed the current state of understanding of origin of life in frank words
"Most chemists believe, as do I, that life emerged spontaneously from mixtures of molecules in the prebiotic Earth.How? I have no idea. Perhaps it was by the spontaneous emergence of “simple” autocatalytic cycles and then by their combination. On the basis of all the chemistry that I know, it seems to me astonishingly improbable"

Monday, June 29, 2009

GABA receptors as RA and Pain Targets? The Missing Link

Kelley et al proposed a hypothesis for an inefficient GABA signalling system that resulted in unchecked pro-inflammatory cytokine production via the p38 MAP kinase pathway. p38 is a kinase target that regulates the production of inflammatory cytokines TNF, IL-1, IL-6 and PGE2.
TNF, IL-1 and IL-6 are well-validated cytokines for controlling inflammation in rheumatoid arthritis (RA). PGE2 is the important mediator for inflammatory pain. But most of the p38 projects failed to deliver drugs due to CNS toxicity, Is this CNS side effects linked to GABA?

The research team led by Ulrich Zeilhofer used genetically altered mice in experiments to target the GABA receptors that control spinal pain relay, they showed that the non-sedative benzodiazepine ligand L- 838417 (a GABA receptor ligand) is highly effective against inflammatory and neuoapathic pain.

Clomethiazole edisilate is a drug that act on GABA receptor, which inhibits the p38 MAPK too. The small molecule doesn’t have the structural features of the other p38 inhibitors have, seems to provide the support for this hypothesis. The task is to find which subtype of GABA responsible for the chronic pain.

However no direct link has been reported between GABA and p38 MAPK.
The role of GABA in the development of RA and pain will encourage the further integration of Immunology in to clinical neuroscience. These finding may provide a rational basis for the development of subtype selective GABAergic drugs for the treatment of RA and chronic pain.

Wednesday, May 13, 2009

Drug Optimization (Lead Optimization?)

Pharmaceutical Companies are trying to fill their drug portfolio by optimizing the marketed drugs. Most of the recently launched drugs that are structurally similar to already known drugs, with only minor differences.The most common drug optimization methods are:

1. Reactive metabolites

A good example of this is venlafaxine (Effexor) and desvenlafaxine ( Pristiq). Desvenlafaxine is the metabolite of venlafaxine. The difference is that desvenlafaxine having O-H instead of O-Me.

2. Switching a Hydrogen atom with heavier isotopes

Pharma companies hopes that the deuterated drug survives longer in the body and fewer side effects, because the Deuterium can make stronger chemical bond than Hydrogen.

3. Racemic switching

Racemic switching is the redevelopment in a single enantiomer from a drug that was fist approved as a racimate, a better example is the Nexium. It is a predecessor Prilosec, a mixture of both S and R isomers. When Prilosec’s patent expired in 2001, the drug maker was ready with Nexium, which contains only the S-isomer.

The proliferation of "me-too" drugs leads to beneficial cost reductions.
But in the end, the real question is about pharmaceutical innovation. While “me too” fill the development pipeline; the creativity is fading away in the Art of Drug Discovery.

Wednesday, April 8, 2009

Rule of attraction

The role of fluorine in Ligand – Protein interaction has been well studied, but much less known about the non-bonding interaction of chlorine and bromine with protein.
A new paper (Angew. Chem. Int. Ed 2009, 48, 2911) from Matter demonstrates the non-covalent interaction between the chlorine or bromine and the aromatic ring in protein.

This Cl/Br…pi interaction might be general use in structure based design towards interaction for aromatic amino acids. It is clear that systematic halogen scan (F, Cl and Br) in the lead structure will be a useful strategy for the lead optimization, not only block the metabolic labile position but also to strengthen protein-ligand binding interaction.

Friday, April 3, 2009

Fluorine in Drug Development

The Drug development process (fig. 2) is a lengthy, high risk and costly endeavor; many strategies exist to accelerate the target to clinical candidate selection as well as to provide the highest quality of the candidate.

Fluorine and its isotope have many role in the different phases of drug development process. The number of fluorine containing drugs are growing rapidly which include the best selling drugs such as Atorvastatin, Prozac, Ciprobay and Pantoprazole (fig.1).

Target Identification

PET is a nuclear medicine imaging tool which allows three- dimentional quantitative determination of the distribution of radioactive whin the human body.The relatively long half life, high % of β emmision and relatively low positron energy maks 18 F makes it is most favourabe for the Positron emission tomography (PET) Studies.
F MR allows detection of the presence of the target, in vivo, includeing assessment of the presence of targets, as well as quantification of their spatial and temporal distribution.

(fig. 2)

F MR - Fluorine Magnetic Resonance.
PET- Positron emission tomography.

Lead Finding

Once the target is chosen and identified, the next stage is typically high-throughput screening of large libraries of chemicals for their ability to modulate the target. F M R allows compound screening using cell based and animal based assays (whereas HTS restricted to cell based assays).
Fluorine plays an important role in the physicochemical properties (see lead optimization) of the molecule so the HTS screening of Fluorine containing libraries will help for the lead finding.

Lead Optimization

The small and highly electronegative fluorine atom can play a role in medicinal chemistry. Systematic Fluorine scan of ligands is a promising strategy in lead optimization. it not only helps to enhance the physicochemical properties but also to strengthen Protein –Ligand binding interaction. This would make the molecule a safer candidate.
The current strategies for introducing fluorine atoms in to molecules are centred to
1. Improve metabolic stability.
2. Alter physicochemical properties such as pKa and lipophilicity, dipole moment and even the chemical reactivity and stability of the neighboring functional groups.
3. Enhance the binding efficacy and selectivity in pharmaceuticals.
4. Bioisosterism.

Preclinical and Clinical Studies

The suboptimal pharmacokinetics and pharmacodynamic can lead up to 40% of the drug candidate failing to make it to phase 1 trial. PET can allow assessment of parameters such as drug absorption biodistribution, metabolism, delivery and dose uses in preclinical studies and can help in systematic planning latter phases.

The estimation of pharmacological agents to reache its targets is important in drugs trials. This can be done by the ADME techniques based on blood or tissue harvesting and subsequent drug and metabolite analysis. This approach is less than a prefect because plasma levels of compound often do not reflect concentrations in specific tissue, because of the presence of physicochemical barriers such as between blood and brain.
Proton Emission tomography provide the reliable measure of tissue drug concentration.


1) Muller. K et al, Science. 317, 2007, 1881.
2) Reid G. D et al, Drug discovery today. 13, 2008, 473.
3) Willmann J. K. et al, Nature reviews drug discovery. 7, 2008, 591.

Friday, March 20, 2009

The rule 2-0

Recently Aronov from Vertex pharmaceuticals proposed (JMC, 2008, 51,1214) a general ‘rule of thumb’ termed the 2-0 rule of kinase likeness to discriminating kinase compound from general compound .

For kinase activity the molecule should have

1) One or more hetero aromatic nitrogen’s
2) One or more hetero aromatic NH group
3) It contain one or more aniline
4) And it contain one or more nitriles

78 % of the kinase compound pass the 2-0 rule.

Saturday, March 14, 2009

Are Protein Kinase Drug Targets ?

20 –25% of druggable genome consists of kinase and this target account 20-30% of the drug discovery program of many companies.

Chem Med Chem 2007, 2,1116

Kinase inhibitors in the market include Tykerb® , Sprycel®, Sutent®,Nexavar®, Tarceva®, Iressa®, and of course Gleevec®.
D&MD Report 2005 shows that, Kinase targeted therapies 12.7bn 2005 to 58.6bn 2010, The key word search for kinase inhibitors 1281 patent filed in 2007 alone.

So what is the problem with kinase? Staurosporine that hits almost every kinase out there is going to be undoubtedly gratuitously toxic, Is "lake of selectivity" is the problem?
The real problem with kinase inhibitors is that toxic outcome may be the result of tissue distribution of orally administered kinase inhibitors.

The Answer is Yes! but,difficult one..

Thursday, January 29, 2009

Phosphonium Coupling

A recent review article,Eur. J. Org. Chem. 2009, 461-479 by Kang F. et al., describes a new, efficient, chemoselective and versatile phosphonium mediated tautomerization-activation methodology for tautomerizable heterocycles.

Phosphonium Coupling affords the direct C-N, C-S, C-O and C-C bond formation of electron deficient heterocycles with various nucleophiles (with boronic acid for C-C) via C-OH bond activation using phosphonium salts.
The author believes that the reactivity of the C-OP+ is similar to that of C-Br, so that direct bond formation can be achieved via either SNAr displacement or transition metal catalyzed cross coupling under mild condition.

This Phosphonium Coupling leads to the most efficient synthesis of biologically important nucleosides from unactivated, unprotected, commercially available starting materials.