1,2,3,4-tetrahydroquinoline is a member of the class of quinolines that is the 1,2,3,4-tetrahydro derivative of quinoline. 1,2,3,4-Tetrahydroquinoline moieties are commonly occurring substructures in a large number of biologically active compounds.

Syntheses of 1,2,3,4-Tetrahydroquinolines using Domino Reactions

A review of the recent literature is given focusing on synthetic approaches to 1,2,3,4-tetrahydroquinolines, 2,3-dihydro-4(1H)-quinolinones and 4(1H)-quinolinones using domino reactions. The 1,2,3,4-tetrahydroquinoline nucleus is a prevalent core structure in a myriad of synthetic pharmaceuticals as well. Nicainoprol is an antiarrhythmic drug, oxamniquine is a schistosomicide, and virantmycin is an antiviral antibiotic that also possesses antifungal activity. Additionally, compound is being evaluated for use in the treatment of HIV, compound 1 is garnering attention as an agent to slow the onset of Alzheimer’s disease, and compound 2 is currently undergoing testing as an antimalarial agent.[1]

Che and co-workers recently disclosed a metal-mediated heterocyclization of it involving an intramolecular nitrene C-H insertion process promoted by the commercially available, air-stable [Fe(III)(F20TPP)Cl] complex [F20TPP = meso-tetrakis(pentafluorophenyl)porphyrinato dianion]. The process offered a one-step route to a limited selection of 2-aryl-1,2,3,4-tetrahydroquinolines in 72%–81% yields. The proposed mechanism involved sequential formation of iron-nitrene complex.  Operational simplicity, excellent atom economy, and low H2 pressures were advantages of this process, but the required use 10 wt% of 10% Pd/C was a drawback. In ethanol solvent, some of the acetaldehyde likely existed as the diethyl acetal, which upon loss of ethanol, would give ethyl vinyl ether. Addition of this vinyl ether to the imine derived from 3-methylaniline and acetaldehyde, would then deliver 4-ethoxy-2,7-dimethyl-1,2,3,4-tetrahydroquinoline

1,2,3,4-Tetrahydroquinoline-Based Selective Human Neuronal Nitric Oxide Synthase

Consequently, the inhibition of nNOS has the potential to be therapeutic in many disease states, but in order to maintain the important roles of eNOS in regulating blood pressure and iNOS in immune responses, the selective inhibition of nNOS is crucial.The discovery of nitric oxide (NO) as a mediator of vascular tone in the early 1980s has led to the unraveling of the diverse biological functions of NO. Numerous studies have shown that selective nNOS inhibitors could be therapeutic in many neurological disorders. Previously, we reported a series of 1,2,3,4-tetrahydroquinoline-based potent and selective nNOS inhibitors. To optimize the properties, we synthesized a small focused library containing various alkylamino groups on the 1-position of the 1,2,3,4-tetrahydroquinoline scaffold. The compounds were triaged based on their activity in the NOS and hERG manual patch clamp assays and their calculated physicochemical parameters.[2]

In brief, this model featured a guanidine isosteric group and a basic amine side chain attached to a central scaffold. In our previous publication, we prepared a number of analogues based on the 1,2,3,4-tetrahydroquinoline core with a thiophene amidine group attached at the 6-position and a variety of acyclic and cyclic alkylamino side chains attached at the 1-position of this scaffold. To achieve this objective, a small focused library was prepared by varying the nature of the aminoalkyl side chain while keeping the 1,2,3,4-tetrahydroquinoline core and thiophene amidine group constant. From our previous work using the 1,2,3,4-tetrahydroquinoline scaffold, the nature of the aminoalkyl side chain did not play a major role in the nNOS inhibitory potency and selectivity.  As observed previously, despite the diverse nature of the aminoalkyl side chains, the differences in inhibitory potencies against nNOS for all compounds are within 0.5 log unit, demonstrating that the aminoalkyl substituents on the 1-position of the 1,2,3,4-tetrahydroquinoline core occupy a fairly tolerant region in the nNOS enzyme.

Synthesis of Novel 1,2,3,4-Tetrahydroquinoline Derivatives

Plant fungal diseases lead to the decline of crop quality and yield, causing huge losses to crop production. In addition, some pathogenic fungi can also cause harm to animal and human health owing to their mycotoxins. Many commercial pesticides are directly or indirectly derived from natural products. Structural modification of natural products is one of the most effective methods to develop novel green pesticides. It is reported that 1,2,3,4-tetrahydroquinoline (THQ), which is widely distributed in natural products, shows good activities such as antitumor activities, antimalarial activities, antivirus activities, and so on.[3]

A series of novel 1,2,3,4-tetrahydroquinoline derivatives containing a pyrimidine ether scaffold were designed and synthesized through the active substructure splicing method. All of the synthesized compounds displayed considerable antifungal activity, particularly against V. mali and S. sclerotiorum. Notably, among all compounds, 4fh showed the highest in vitro activity against V. mali and S. sclerotiorum with the EC50 values of 0.71 and 2.47 μg/mL, respectively. Subsequently, a reliable 3D-QSAR model was established to guide the further optimization of novel 1,2,3,4-tetrahydroquinoline derivatives with higher activity.  Furthermore, the in vivo activity of compound 4fh against S. sclerotiorum was evaluated to confirm its potential role in controlling rape sclerotinia stem rot. In addition, SEM and TEM were applied to reveal the 1,2,3,4-tetrahydroquinoline derivatives may be potential inhibitors against CHS. Compound 4fh had displayed certain inhibition activity against CHS at a concentration of 50 μM, which was even better than that of the positive control polyoxin D.

References

[1]Nammalwar B, Bunce RA. Recent syntheses of 1,2,3,4-tetrahydroquinolines, 2,3-dihydro-4(1H)-quinolinones and 4(1H)-quinolinones using domino reactions. Molecules. 2013 Dec 24;19(1):204-32. doi: 10.3390/molecules19010204. PMID: 24368602; PMCID: PMC6271761.

[2]Ramnauth J, Renton P, Dove P, Annedi SC, Speed J, Silverman S, Mladenova G, Maddaford SP, Zinghini S, Rakhit S, Andrews J, Lee DK, Zhang D, Porreca F. 1,2,3,4-tetrahydroquinoline-based selective human neuronal nitric oxide synthase (nNOS) inhibitors: lead optimization studies resulting in the identification of N-(1-(2-(methylamino)ethyl)-1,2,3,4-tetrahydroquinolin-6-yl)thiophene-2-carboximidamide as a preclinical development candidate. J Med Chem. 2012 Mar 22;55(6):2882-93. doi: 10.1021/jm3000449. Epub 2012 Mar 1. PMID: 22335555.

[3]Zhang, X., Yang, Z., Xu, H., Liu, Y., Yang, X., Sun, T., Lu, X., Shi, F., Yang, Q., Chen, W., Duan, H., & Ling, Y. (2022). Synthesis, Antifungal Activity, and 3D - QASR of Novel 1,2,3,4 - Tetrahydroquinoline Derivatives Containing a Pyrimidine Ether Scaffold as Chitin Synthase Inhibitors. Journal of Agricultural and Food Chemistry, 70(30), 9262 - 9275.