Synthetic (E)-3-Phenyl-5-(phenylamino)-2-styryl-1,3,4-thiadiazol-3-ium Chloride Derivatives as Promising Chemotherapy Agents on Cell Lines Infected with HTLV-1

Abstract

Synthesis of four compounds belonging to mesoionic class, (E)-3-phenyl-5-(phenylamino)-2-styryl-1,3,4-thiadiazol-3-ium chloride derivatives (5a–d) and their biological evaluation against MT2 and C92 cell lines infected with human T-cell lymphotropic virus type-1 (HTLV-1), which causes adult T-cell leukemia/lymphoma (ATLL), and non-infected cell lines (Jurkat) are reported. The compounds were obtained by convergent synthesis under microwave irradiation and the cytotoxicity was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Results showed IC50 values of all compounds in the range of 1.51–7.70 μM in HTLV-1-infected and non-infected cells. Furthermore, it was observed that 5b could induce necrosis after 24 h for Jurkat and MT2 cell lines. The experimental (fluorimetric method) and theoretical (molecular docking) results suggested that the mechanism of action for 5b could be related to its capacity to intercalate into DNA. Moreover, the preliminary pharmacokinetic profile of the studied compounds (5a–d) was obtained through human serum albumin (HSA) binding affinity using multiple spectroscopic techniques (circular dichroism, steady-state and time-resolved fluorescence), zeta potential and molecular docking calculations. The interaction HSA:5a–d is spontaneous and moderate (Ka ~ 104 M−1) via a ground-state association, without significantly perturbing both the secondary and surface structures of the albumin in the subdomain IIA (site I), indicating feasible biodistribution in the human bloodstream.

Vanadium(v) complexes derived from triphenylphosphonium and hydrazides: cytotoxicity evaluation and interaction with biomolecules

“…On the other hand, for HSA, there are three main binding pockets for both endogenous and exogenous compounds: subdomain IIA (site I) located in a hydrophobic binding pocket, subdomain IIIA (site II), also located in a hydrophobic binding pocket, and subdomain IB (site III) located on the surface of the albumin. 48,71,72 All binding sites are able to accommodate the vanadium( v ) complexes, however, site III is the main pocket according to the molecular docking score values (Table 4). Reported in silico data indicated site I or site III as the main binding pockets for the interaction between HSA and some V V -complexes derived from pyridoxal or salicylaldehyde, 31,57 suggesting a dependence on the nature of the ligands in the interactive profile with albumin.…”

New Perspectives about Drug Candidates Targeting HTLV-1 and Related Diseases

“…One of the compounds induced necrosis after 24 h in Jurkat and MT-2 cell lines. The experimental (fluorimetric method) and theoretical (molecular docking) results suggested that the mechanism of action could be related to its capacity to intercalate into DNA, and they presented spontaneous and moderate interaction with albumin in human serum albumin (HSA)-binding affinity assay by multiple spectroscopic techniques (circular dichroism, steady-state and time-resolved fluorescence), zeta potential, and molecular docking calculations, indicating good biodistribution in the human bloodstream (Table 1) [23].…”

“…The compounds with electron donor substituents (R=CH3 or OCH3) were more active, showing cell death by necrosis, interacting with DNA, and exhibiting lower hydrophobicity. Also, the preliminary pharmacokinetic profile obtained through human serum albumin (HSA) binding affinity using multiple spectroscopic techniques, zeta potential, and molecular docking calculations revealed that all the mesoionic compounds presented good binding parameters toward serum albumin, indicating feasible biodistribution in the human bloodstream (Table 2) [23].…”

“…Pharmacokinetic profile of the compounds was obtained through human serum albumin (HSA) binding affinity using multiple spectroscopic techniques (circular dichroism, steady-state and time-resolved fluorescence), zeta potential, and molecular docking calculations. [23] Anti-CD70 single-chain Fv-Fc antibody conjugated with emtansine Showed selective killing of peripheral blood mononuclear cells (PBMCs) from an ATLL patient.…”

Synthesis, Spectral Characteristics, and Molecular Docking Studies of 2,4-Dichloro-N-(2,2,2-trichloro-1-((5-(phenylamino)-1,3,4-thiadiazol-2-yl)amino)ethyl)benzamide

“…These compounds are of particular interest as biologically active compounds [2]. Among the derivatives of 1,3,4-thiadiazole are substances with antitumor [3][4][5][6][7][8][9][10][11], antiviral [11][12][13][14][15][16][17], antimicrobial [10,[18][19][20][21][22][23][24][25][26][27][28][29][30], antioxidant [29,30], neuroprotective [31], antiprotozoal [32], and anti-inflammatory [33,34] activity. In addition, these substances act as inhibitors of acetylcholinesterase [35,36], αglucosidase [37], and carbonic anhydrase [38].…”