TY - JOUR
T1 - Recent advances in the medicinal chemistry of phenothiazines, new anticancer and antiprotozoal agents
AU - Gonzalez-Gonzalez, Alonzo
AU - Vazquez-Jimenez, Lenci K.
AU - Paz-Gonzalez, Alma D.
AU - Bolognesi, Maria Laura
AU - Rivera, Gildardo
N1 - Publisher Copyright:
© 2021 Bentham Science Publishers.
PY - 2021/11
Y1 - 2021/11
N2 - Background: Molecules with a phenothiazine scaffold have been considered versatile organic structures with a wide variety of biological activities, such as antipsychotic, anticancer, antibacterial, antifungal, antiviral, anti-inflammatory, antimalarial, and trypanocidal, etc. It was first discovered in the 19th century as a histochemical dye, phenothiazine methylene blue. Since then, its derivatives have been studied, showing new activities; moreover, they have also been repurposed. Objective: This review aims to describe the main synthetic routes of phenothiazines and, particularly, the anticancer and antiprotozoal activities reported during the second decade of the 2000s (2010 - 2020). Results: Several studies on phenothiazines against cancer and protozoa have revealed that these compounds show IC50 values in the micromolar and near nanomolar range. The structural analyses have revealed that compounds bearing halogens or electron-withdrawing groups at 2-position have favorable anticancer activity. Phenothiazine dyes have shown a photosensitizing activity against trypanosomatids at a micromolar range. Tetra and pentacyclic azaphenothiazines are structures with a high broad-spectrum anticancer activity. Conclusion: The phenothiazine scaffold is favorable for developing anticancer agents, especially those bearing halogens and electron-withdrawing groups bound at 2-position with enhanced biological activities through a variety of aromatic, aliphatic and heterocyclic substituents in the thiazine nitrogen. Further studies are warranted along these investigation lines to attain more active anticancer and antiprotozoal compounds with minimal to negligible cytotoxicity.
AB - Background: Molecules with a phenothiazine scaffold have been considered versatile organic structures with a wide variety of biological activities, such as antipsychotic, anticancer, antibacterial, antifungal, antiviral, anti-inflammatory, antimalarial, and trypanocidal, etc. It was first discovered in the 19th century as a histochemical dye, phenothiazine methylene blue. Since then, its derivatives have been studied, showing new activities; moreover, they have also been repurposed. Objective: This review aims to describe the main synthetic routes of phenothiazines and, particularly, the anticancer and antiprotozoal activities reported during the second decade of the 2000s (2010 - 2020). Results: Several studies on phenothiazines against cancer and protozoa have revealed that these compounds show IC50 values in the micromolar and near nanomolar range. The structural analyses have revealed that compounds bearing halogens or electron-withdrawing groups at 2-position have favorable anticancer activity. Phenothiazine dyes have shown a photosensitizing activity against trypanosomatids at a micromolar range. Tetra and pentacyclic azaphenothiazines are structures with a high broad-spectrum anticancer activity. Conclusion: The phenothiazine scaffold is favorable for developing anticancer agents, especially those bearing halogens and electron-withdrawing groups bound at 2-position with enhanced biological activities through a variety of aromatic, aliphatic and heterocyclic substituents in the thiazine nitrogen. Further studies are warranted along these investigation lines to attain more active anticancer and antiprotozoal compounds with minimal to negligible cytotoxicity.
KW - Anticancer
KW - Antiprotozoal
KW - Biological activities
KW - Drugs
KW - Phenothiazine
KW - Scaffold
UR - http://www.scopus.com/inward/record.url?scp=85120932839&partnerID=8YFLogxK
U2 - 10.2174/0929867328666210405120330
DO - 10.2174/0929867328666210405120330
M3 - Artículo
C2 - 33820509
AN - SCOPUS:85120932839
SN - 0929-8673
VL - 28
SP - 7910
EP - 7936
JO - Current Medicinal Chemistry
JF - Current Medicinal Chemistry
IS - 38
ER -