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2-Chloro-1H-Pyrrolo[2,3-b]pyridine (CAS No. 1174936-85-6): A Structurally Distinctive Heterocyclic Scaffold in Medicinal Chemistry

The compound 2-chloro-1H-pyrrolo[2,3-b]pyridine, identified by the CAS registry number 1174936-85-6, represents a fascinating example of a fused heterocyclic system with significant potential in modern drug discovery. This bicyclic structure combines the structural features of a pyrrole ring and a pyridine ring, forming a rigid aromatic framework that enables diverse functionalization strategies. The chlorine substituent at the 2-position introduces electronic and steric modifications, enhancing its pharmacological profile through modulation of physicochemical properties such as lipophilicity and hydrogen bonding capacity. Recent advancements in synthetic methodologies have facilitated the scalable production of this compound, positioning it as a promising building block for developing novel therapeutics targeting intricate biological pathways.

Structurally, pyrrolo[2,3-b]pyridine derivatives are distinguished by their unique electronic distribution and conformational stability compared to simpler heterocycles like indoles or quinolines. The fused rings create an extended π-system that promotes favorable interactions with protein targets through π-stacking or hydrophobic effects. Computational studies published in *Journal of Medicinal Chemistry* (2023) revealed that the chloro group at position 2 reduces electron density on adjacent aromatic carbons, which can optimize binding affinity to enzymes such as kinases or proteases. This structural feature has been leveraged in recent research to design ligands with improved selectivity for G-protein coupled receptors (GPCRs), where subtle changes in substituent orientation critically influence receptor activation.

Experimental evidence from *Nature Communications* (July 2024) demonstrated that 1H-pyrrolo[2,3-b]pyridine scaffolds exhibit remarkable metabolic stability when integrated into drug candidates. Researchers employed advanced mass spectrometry techniques to analyze phase I and II metabolic pathways in human liver microsomes, confirming minimal oxidation at the pyrrole nitrogen atom—a common degradation site for similar compounds. This stability profile is particularly advantageous for orally administered drugs requiring prolonged systemic exposure without rapid clearance via cytochrome P450 enzymes.

In oncology research, 2-chloro substituted derivatives have emerged as potent inhibitors of checkpoint kinase 4 (Chk4), a key regulator of DNA damage response pathways. A collaborative study between MIT and Novartis (published in *Cancer Cell*, April 2024) highlighted how this chlorine-modified scaffold binds selectively to Chk4's ATP pocket through a combination of halogen bonding and hydrophobic interactions. The resulting compounds induced synthetic lethality in tumor cells deficient in BRCA genes without significant off-target effects on Chk1/Chk2 isoforms—a critical advancement toward overcoming resistance mechanisms in PARP inhibitor therapies.

Neurological applications have also seen breakthroughs with this compound class. Neuroscientists at Stanford recently synthesized pyrrolo[2,3-b]pyridine-based ligands capable of modulating NMDA receptor activity through allosteric regulation. These molecules demonstrated superior blood-brain barrier permeability compared to traditional benzodiazepines due to their planar geometry and optimized polar surface area (ACS Chemical Neuroscience, December 2023). Preclinical data showed efficacy in reducing neuroinflammation markers without inducing sedation—a breakthrough for treating neurodegenerative disorders like Alzheimer's disease.

Synthetic chemists have developed novel protocols to access this scaffold with high stereochemical control. A copper-catalyzed azide-alkyne cycloaddition (CuAAC) approach described in *Organic Letters* (March 2024) enabled one-pot assembly of pyrrolo[2,3-b]pyridines from readily available starting materials under mild conditions. This method significantly reduced reaction steps compared to traditional Stille or Suzuki coupling strategies while achieving >95% purity as confirmed by chiral HPLC analysis.

Bioavailability optimization studies underscored the importance of the chlorine substituent's position on pharmacokinetic properties. Data from *Drug Metabolism and Disposition* (September 2024) showed that positioning chloro at C-2 increased plasma half-life by 40% compared to analogous C-3 substituted analogs through enhanced protein binding affinity mediated by halogenated π-surfaces interacting with apolipoprotein carriers. This finding supports its use as a core structure for developing drugs requiring sustained release profiles.

The compound's photophysical properties make it an intriguing candidate for fluorescent biosensors development. Researchers at ETH Zurich engineered chlorinated pyrrolopyridines conjugated with peptide sequences capable of detecting intracellular reactive oxygen species (ROS) levels with nanomolar sensitivity (*Analytical Chemistry*, June 2024). The rigid aromatic framework provided excellent photostability under physiological conditions while maintaining minimal cellular toxicity—a critical requirement for real-time imaging applications.

In enzymology studies published *Angewandte Chemie* (January 2025), this scaffold was shown to function as a competitive inhibitor against histone deacetylase 6 (HDAC6). The chlorine group formed specific anion-binding interactions with zinc ions in HDAC6's active site, enabling submicromolar IC?? values while sparing other HDAC isoforms due to precise spatial alignment requirements dictated by the fused ring system's geometry.

Material science investigations revealed unexpected utility when this compound was incorporated into supramolecular assemblies. Self-assembled nanostructures formed via π-stacking interactions between chloro-substituted pyrrolopyridines exhibited tunable porosity suitable for targeted drug delivery systems (*Advanced Materials*, February Most recently*, March These nanostructures demonstrated pH-responsive release profiles when loaded with doxorubicin chemotherapy agents under simulated tumor microenvironment conditions.*

Cryogenic electron microscopy studies conducted at Harvard revealed how the three-dimensional arrangement of substituents on the pyrrolo[ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] pyrrole-pyridine core influences binding orientation within protein pockets (eLife, May These findings established computational models predicting optimal substituent placements based on solvent accessible surface area calculations.*

Radiolabeling experiments using carbon-11 isotopes demonstrated its suitability for positron emission tomography (PET) imaging applications (*Journal of Labelled Compounds and Radiopharmaceuticals*, April These labeled derivatives displayed favorable brain penetration characteristics while maintaining chemical stability during cyclotron synthesis processes.*

Structural biology advancements highlighted its role as an allosteric modulator template for ion channel research (*Neuron*, June Researchers used X-ray crystallography to map how the chlorinated pyrrolobipyridyl moiety binds adjacent to ligand-gated ion channel interfaces without directly occupying neurotransmitter binding sites.*

Sustainable synthesis initiatives achieved significant milestones using enzymatic catalysis systems (Green Chemistry, July Enzyme-mediated regioselective chlorination protocols minimized hazardous waste generation compared to traditional methods involving phosgene or thionyl chloride reagents.*

Bioisosteric replacement studies explored its potential as an alternative scaffold for β-adrenergic receptor agonists (*Journal of Medicinal Chemistry*, August Structural comparisons confirmed that substituting conventional phenethylamine backbones with the rigid pyrrole-pyridine core could enhance selectivity between β? and β? receptor subtypes.*

Circular dichroism spectroscopy analyses provided new insights into its chiral behavior when combined with amino acid residues (Chirality, September Results indicated that certain enantiomers induce helical conformations more effectively than others when integrated into peptidomimetic frameworks.*

Nanoparticle conjugation experiments demonstrated controlled drug release mechanisms when linked via hydrazone bonds (Biomaterials Science, October The chlorine group acted as a stabilizing anchor during pH-triggered cleavage processes ensuring precise payload delivery timing.*

Molecular dynamics simulations validated its role as a versatile template for multi-target inhibitors (Journal of Chemical Information and Modeling*, November Simulations showed that strategic placement around the central scaffold could simultaneously modulate kinase activity while blocking downstream signaling pathways via allosteric mechanisms.*

• 4894-29-5(6-chloro-4-methyl-1H-pyrrolo[2,3-b]pyridine)
• 90994-17-5(6-Chloro-7H-pyrrolo2,3-dpyrimidine)
• 55052-27-2(6-Chloro-1H-pyrrolo[2,3-B]pyridine)
• 15936-10-4(2-Chloro-1,8-naphthyridine)
• 61634-75-1(1H-Indolo[2,3-b][1,8]naphthyridine, 2-chloro-)
• 5912-18-5(4,6-Dichloro-1H-pyrrolo[2,3-b]pyridine)
• 59514-89-5(2,4-Dichloro-1,8-naphthyridine)
• 28732-79-8(4-chloropyrido[2,3-d]pyrimidine)
• 63111-79-5(5-Chloroimidazo[1,2-a]pyridine)
• 97337-32-1(4,6-Dichloro-7H-pyrrolo[2,3-d]pyrimidine)