RSC Advances View Article Online REVIEW View Journal | View Issue Synthesis and biological activities of local anesthetics Cite this: RSC Adv.,2019,9, 41173 Shiyang Zhou,a Gangliang Huang *b and Guangying Chen*a Local anesthetics are mainly used in stomatology, ophthalmology, gynecology and surgery to temporarily relieve pain. Local anesthetics act on nerve endings or around nerve trunks, and are combined with specific sodium ion (Na+) channel sites on the nerve membrane. They can affect the membrane potential by reducing Na+ passage through sodium ion channels, thus blocking the generation and conduction of Received 8th November 2019 nerve impulses, reversibly blocking the generation and conduction of sensory nerve impulses. Local Accepted 27th November 2019 anesthetics are used for convenience in local surgical operations and treatments. Herein, we mainly DOI: 10.1039/c9ra09287k review the research progress on local anesthetics and discuss the important aspects of design, synthesis rsc.li/rsc-advances and biological activity of various new compounds. – Creative Commons Attribution-NonCommercial 3.0 Unported Licence. 1. Introduction which is mainly used before surgery.8 11 In contrast, local anesthetics act on nerve endings or around nerve trunks, Anesthetics are a type of drug that act on the nervous system, reversibly blocking the generation and conduction of sensory causing it to be inhibited and resulting in the loss of the sense nerve impulses, and temporarily eliminating local sensation of pain.1–4 According to the different scopes of action of drugs, (mainly pain sensation) under the condition of consciousness. the department of anesthetics is divided into general anes- Moreover, it is convenient for local surgical operations and – thetics and local anesthetics.5–7 General anesthetics act on the treatments.12 14 Local anesthetics are mainly used in stomatol- central nervous system, causing it to be reversibly inhibited, ogy, ophthalmology, gynecology and surgery to relieve pain thereby resulting in a loss of consciousness and sensation. temporarily.15 Local anesthetics combine with specic sodium This article is licensed under a Especially pain sensation and reexes disappear and skeletal ion (Na+) channel sites on the nerve membrane, and they can muscle relaxes, thus achieving the effect of general anesthesia, affect the membrane potential by reducing Na+ passage through the sodium ion channels, thus blocking the generation and 16 Open Access Article. Published on 13 decembris 2019. Downloaded 24.09.2021 22:07:32. a conduction of nerve impulses. Local anesthetics decrease the Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education, ff College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou excitability of nerve membranes, but have no e ect on their 17–20 571158, China. E-mail: [email protected] resting potential. The application methods of local anes- bActive Carbohydrate Research Institute, Chongqing Key Laboratory of Green Synthesis thesia can be divided into topical anesthesia, invasive anes- and Application, College of Chemistry, Chongqing Normal University, Chongqing thesia, conduction anesthesia, subarachnoid anesthesia and 401331, China. E-mail: [email protected] epidural anesthesia.21–24 The rst local anesthetic used was an active ingredient from coca leaves in South America (Erythroxylum coca Lam.). The Shiyang Zhou is a Research Peruvians were known for chewing coca leaves to relieve pain as Scholar at the College of Chem- early as 1532. In 1860, Niemann extracted an alkaloid crystal istry and Chemical Engineering, from coca leaves and named it cocaine (1). Koller, an Austrian Hainan Normal University, ophthalmologist, rst formally used cocaine in clinical surgery China. He is pursuing PhD in in 1884. Also, he discovered a new local anesthesia technology, chemistry from the Hainan which led to the rapid development of local anesthetics.25–30 Normal University. He has Cocaine has a local anesthesia effect and vasoconstriction received his Master of Science effect, and it can reduce the bleeding of surgical wounds.31–34 degree in Chemical Biology from Additionally, cocaine can be used in the nose, nasopharynx, the Chongqing Normal Univer- mouth, throat and ear as surface anesthesia.35–39 However, sity, China. He has over six years cocaine is highly addictive, and easy to cause tissue irritation, of experience in Industry and allergic reactions and other toxic side effects. Also, its aqueous Academics. His research interests solution is not stable, and thus easily hydrolyzed during high- include the medicinal chemistry (drug design and synthesis, natural pressure disinfection; therefore, the clinical application of products semi-synthesis and full synthesis). This journal is © The Royal Society of Chemistry 2019 RSC Adv.,2019,9, 41173–41191 | 41173 View Article Online RSC Advances Review cocaine is greatly restricted, and it has long since been replaced on the structure of aromatic acid esters, amide, aminoketone, by other local anesthetics.40–43 Because of the shortcomings of aminoether and amino carbamate types of local anesthetics cocaine, researchers began to study and modify the structure of were developed (Table 1). In terms of drugs structure–activity cocaine to nd better local anesthetics. None of the three relationship (SAR), the chemical structure of local anesthetics products from the hydrolysis of cocaine, ecgonine (2), benzoic usually consists of three basic skeleton parts, a lipophilic acid and methanol, has the effect of local anesthesia.44 Substi- aromatic ring, intermediate connecting functional group and tution of benzoic acid with other carboxylic acids can form hydrophilic amine group. In recent years, the local anesthetics esters with ecgonine, resulting in reduced or complete loss of used in clinical practice are mainly used to reduce toxicity and anesthetic effects, proving that benzoic acid esters are an prolong the action time by changing the new dosage forms of important structure of cocaine with local anesthetic effects. The existing local anesthetics.60,61 Herein, we mainly review the alkaloid tropacocaine (3) isolated from the leaves of coca in Java research progress of local anesthetics (2009–2019), including had only the structure of benzoate ester and no carboxylate the design, synthesis and biological activity of various new methyl ester group in its molecular structure, which had the compounds. general effect of local anesthesia. Therefore, the local anes- thesia effect of benzoate ester was further conrmed.45–47 Aer determining the local anesthesia effect of benzoate 2. Synthesis and biological activities ester, the structure of the parent nucleus of cocaine (ecgonine) Local anesthesia is a compound that blocks the conduction of was modied and simplied. When the N-methyl of ecgonine nerve bers when applied locally to nerve tissue at appropriate was removed, there was no signicant effect on physiological concentrations. It blocks the voltage-sensitive sodium channels activities, but the toxicity increased.48 If the nitrogen atom was of each nerve ber, eliminating their action potential. The quaternized, the activity was lost. For ecgonine, Corning further greatest practical advantage of local anesthetics is that their simplied its structure, and designed and synthesized two effects can be reversed when they were removed from nerve a b Creative Commons Attribution-NonCommercial 3.0 Unported Licence. piperidol benzoate derivatives, -eucaine (4) and -eucaine (5). tissue. In this case, nerve function and action potential are Both of them had a local anesthetic effect similar to cocaine, but completely restored, with no evidence of damage to nerve bers their aqueous solution property was relatively stable, and their or cellular structures. Compounds with amino groups linked to toxicity was also low, which indicate that the ecgonine double heterocyclic nuclei, such as lipophilic molecules, were shown to ring structure is not necessary for the local anesthesia effect.49–53 be more active and less toxic than benzene analogues. It has Simultaneously, this further proves the importance of the been reported that 2-aminobenzothiazole, 2-aminothiazole benzoate ester part from the side. Due to the signicant derivatives and 3-aminobenzoazole-[d]-isothiazole derivatives research work on benzoate ester compounds, benzocaine (6) have local anesthetic activity. In 2009, Carla F. et al.62 reported was rst synthesized in 1890 and proven to have a local anes- the design and synthesis of different thiazole and isothiazole This article is licensed under a thesia effect. Subsequently, orthoform (7) and new orthoform derivatives for the study of local anesthesia. In the process of (8) were successfully synthesized. Both of them exhibited strong structural design of target compounds 1–32, they used the local anesthesia effects, but they were not water-soluble and thiazole structure as the parent structure of the target could not be injected.54–56 They could only be used for local Open Access Article. Published on 13 decembris 2019. Downloaded 24.09.2021 22:07:32. compounds, and simultaneously retained the alkyl-acetamido anesthesia, while their salt was too acidic to be used. Because of or alkyl-propionamide groups that local anesthetic drugs their shortcomings, further structural transformation led to the have. In terms of structure–activity relationship (SAR), these successful development of the local anesthetic procaine (9)in target molecules were structurally