Phenothiazine Dopamine Receptor antagonist

Phenothiazines mostly substitutes at position 10 with the dialkylaminoalkyl groups and additionally at position 2 with small groups exhibit valuable activities such as neuroleptic, antiemetic, antihistaminic, antipuritic, analgesic and antihelmintic. 2-trifluoromethyl-10-(4-aminobutyl)phenothiazine inhibits S. cerevisiae strains and T. mentagrophites with MIC of 0.4 μg/mL and 1.5 μg/mL, respectively. 10-carbamoylalkyl derivatives shows significant activities against Gram-positive Bacillus subtilis with MIC’s in the range of 7.8 μg/mL–30 μg/mL. The tetracyclic compounds (modified with the naphthoquinone ring) shows significant actibacterial activity against S. aureus with the MIC50 of 12.5 μg/mL. These compounds with the butylene linker are more effective than with the propylene linker, the 2-chloro-10-chloroethylureidobutyl derivative giving GI50 of 1.4 μM and 1.6 μM against 4 leukemia cell lines and 7 colon cancer cell lines. 10-Amino(hydroxy)propyl derivatives (5 μM) induces a marked G2/M phase of cell-cycle arrest followed by cell death in human transformed WI38VA cells after 2-day incubation. [1] This class of drugs undergo extensive metabolism in the body before being excreted, mainly ring hydroxylation, ring sulphoxidation, N-demethylation, N-oxidation, sulphate and glucuronide conjugation. They have considerably lower binding affinities to α2-adrenoceptors than to dopamine D2 receptors and al-adrenoceptors. [2] These compounds have significant in vitro activity against susceptible, polydrug- and multidrug-resistant strains of M. tuberculosis, as well as enhancing the activity of some agents employed for first-line treatment. [3]