Fused 1,5-Naphthyridines: Synthetic Tools and Applications

Abstract

Heterocyclic nitrogen compounds, including fused 1,5-naphthyridines, have versatile applications in the fields of synthetic organic chemistry and play an important role in the field of medicinal chemistry, as many of them have a wide range of biological activities. In this review, a wide range of synthetic protocols for the construction of this scaffold are presented. For example, Friedländer, Skraup, Semmlere-Wolff, and hetero-Diels-Alder, among others, are well known classical synthetic protocols used for the construction of the main 1,5-naphthyridine scaffold. These syntheses are classified according to the nature of the cycle fused to the 1,5-naphthyridine ring: carbocycles, nitrogen heterocycles, oxygen heterocycles, and sulphur heterocycles. In addition, taking into account the aforementioned versatility of these heterocycles, their reactivity is presented as well as their use as a ligand for metal complexes formation. Finally, those fused 1,5-naphthyridines that present biological activity and optical applications, among others, are indicated.

Biological Activity of Naturally Derived Naphthyridines

“…Until now, research studies revealed their impressive antimicrobial [ 6 , 8 , 177 ], antifungal [ 6 , 8 , 111 , 112 ], and antimycobacterial [ 10 , 178 ] effects, and some of them displayed activity superior or comparable to those presented by chloramphenicol [ 112 ], amphotericin B [ 115 ], and rifampin [ 124 ]—drugs used in standard therapeutic regimens. Moreover, naphthyridines were shown to present significant properties including antiinfectious: antiviral [ 11 , 24 , 50 , 51 ], antiparasitic [ 9 , 176 ], and antimalarial [ 113 ]; anticancer [ 5 , 6 , 23 , 35 ]; influencing cardiovascular system: hypotensive [ 16 , 27 ], cardioprotective [ 43 , 44 ]; neurological: sedative [ 94 ], analgesic [ 15 ], anticonvulsant [ 78 ], stimulating neuritogenesis [ 188 ]; psychotropic: antianxiety [ 97 ], antidepressant [ 29 , 97 ]; and affecting immune system: anti-inflammatory [ 7 , 56 , 57 ], immunosuppressant [ 48 , 49 , 50 ]. The spectrum of activity of naturally-derived naphthyridines is wide, thus these compounds are undeniably fascinating subjects of research.…”

“…Natural products—cimiciduphytine 14 and eburnane derivatives 15 ( Figure 4 )—were evaluated as natural painkillers and antihypertensive agents, which could be used in cerebral circulation disturbance therapy [ 16 ].…”

“…The novel agents 12 and 13 reduced the production of pro-inflammatory mediators: NO, IL-6, and TNF-α in LPS-induced RAW 264.7 cells, with IC 50 values in the range of 20.51-66.96 µM [15]. Natural products-cimiciduphytine 14 and eburnane derivatives 15 (Figure 4)-were evaluated as natural painkillers and antihypertensive agents, which could be used in cerebral circulation disturbance therapy [16].…”

A Four-Component Domino Reaction: An Eco-Compatible and Highly Efficient Construction of 1,8-Naphthyridine Derivatives, Their In Silico Molecular Docking, Drug Likeness, ADME, and Toxicity Studies

“…e naphthyridine framework exists in a number of natural and synthetic substances with various chemical reactivities and exceptional physicochemical [1] and biological properties [2,3], which include anticancer, [4] HIV-I inhibitor, [5] anticonvulsant, [6] antimalarial [7], and anti-Alzheimer [8]. Among the six possible (1,5−, 1,6−, 1,7−, 1,8−, 2,6−, and 2,7−) isomeric pyridopyridines, [9,10] 1,8-naphthyridines and their derivatives have diverse potential in clinical and medicinal chemistry due to their anti-inflammatory, [11] antimalarial, [12] antihypertensive, [13] gastric antisecretory, [14] antiplatelet aggregation, [15] AChE inhibitory, [16] antihistaminic, [2] antimicrobial [17,18], and anticancer [19][20][21] activities (Figure 1).…”

Naphthyridine Derivatives Induce Programmed Cell Death in Naegleria fowleri

“…The naphthyridine (Figure 1) ring has gained attention, becoming an important pharmacophore in the discovery of new biological agents due to its attractive biological activities [29]. In this sense, several naphthyridine derivatives present good pharmacological activity with low toxicity [30]. In addition, among the most cited applications related to 1,8naphthyridines are antiparasitic [31,32], antibacterial [33,34], and antiviral [35][36][37] activities.…”