Heterocyclic compounds as antiviral drugs: Synthesis, structure–activity relationship and traditional applications

Abstract

A virus outbreak challenges the economic, medical, and public health infrastructure worldwide. More than one virus capable of triggering diseases have been identified per year since 1972, which requires the development of new ways of treatment and prevention, however, such processes are not rapid and easy. With the pandemic scenario experienced since early 2020, several drugs with well-known purposes have gained prominence, due to speculation of their use in the treatment against the new coronavirus. Among the main drugs studied, the vast majority contain a heterocyclic structure. In this review, we presented the traditional and efficient synthesis of 15 drugs that have been studied for the COVID-19 treatment, containing in their structure heterocycles like indole, quinoline, pyrimidone, tetrahydrofuran, pyrrolidine, triazole, pyridazine, pyrazole, pyrrolopyrimidine, azetidine, pyrrolotriazine, pyrazine, tetrahydropyran, benzofuran, spiroketal, and thiazole. Furthermore, we have shown the original applications, as well as their structure-activity relationship and what is their situation as a drug candidate against COVID-19. Thus, the objective was to consolidate the main synthetic and pharmacological aspects involving clinically developed heterocycles that at some point were presented as promising against SARS-CoV-2.

Design, synthesis, and biological activity of heterocyclic methyl esters

“…The heterocycle moieties were demonstrated for interaction with the target site in medicinal chemistry and biochemistry [1–3]. Chemical active ingredients usually give excellent antibacterial, anti‐inflammatory, and anti‐tumor activities if structurally introduced or replaced by heterocyclic fragments [4–6]. In pesticide chemistry, many insecticides, herbicides, and fungicides are structured with five or six‐membered heterocyclic rings, for example, fipronil, and ethiprole contain pyrazole structure, boscalid, and fluopyram characters with pyridine group, and thifluzamide comprises furan moiety.…”

Regiospecific Reduction of 4,6‐Dinitrobenzimidazoles: Synthesis, Characterization, and Biological Evaluation

“…Various N-heterocyclic antiviral drugs such as ribavirin, zidovudine, remdesivir, and paxlovid became prominent examples in the course of the recent pandemics. [6] The quinoline alkaloids quinine, chloroquine, and mefloquine are efficient treatments for protozoal parasite infections such as malaria, while nitro-substituted Nheterocycles like metronidazole are clinically applied for the treatment of amoebiasis, giardiasis, etc. [7,8] The trypanocidal drugs fexinidazol (applied for the treatment of sleeping sickness) and benznidazole (a drug against Chagas disease) are further prominent examples of antiparasitic imidazoles.…”

“…N ‐Heterocycles are likewise valuable drugs against several infectious diseases. Various N ‐heterocyclic antiviral drugs such as ribavirin, zidovudine, remdesivir, and paxlovid became prominent examples in the course of the recent pandemics [6] . The quinoline alkaloids quinine, chloroquine, and mefloquine are efficient treatments for protozoal parasite infections such as malaria, while nitro‐substituted N ‐heterocycles like metronidazole are clinically applied for the treatment of amoebiasis, giardiasis, etc [7,8] .…”

Computational Insights and Virtual Screening of Repurposed FDA-Approved Drug Against SARS-CoV-2 Protease

“…The protein main protease ( M pro ) encoded inside the viral genome of SARS-CoV-2 is chosen as the target of interest in the present investigation, whose crystal structure is available in the literature (PDB ID: 6LU7) (Bzowka et al 2020 ) but as a covalently bound complex (Hatada et al 2020 ) with N3 inhibitor. Recent literature reports show that most of the antiviral drugs contain heterocyclic rings since drugs with such moieties have been observed to show potent antiviral property against SARS-CoV-2 (Negi et al 2020 ; Carvalho dos Santos et al 2021 ; Elsaman et al 2022 ; De et al 2021 ; Garg et al 2020a ).…”