In vitro Antiproliferative Properties of Lipophililic-Acid Chelating Fluoroquinolones
and TriazoloFluoroquinolones with 7-dihaloanilinosubstitution
Authors: Hallaq Tasneem , Al-Hiari Yusuf , Kasabri Violet , AlBashiti Rabab , AlAlawi Sundus , Telfah Ahmad 
Published: May 2022

Background:
Incidence rates and prevalence of cancer are substantially high globally. New safe therapeutic
drugs are endorsed to overcome the high toxicity and poor safety profile of clinical anticancer agents.

Objectives:
As antineoplastic Vosaroxin is a commercial fluoroquinolone (FQ), we hypothesize that superlative antiproliferation
activity of lipophilic FQs/TFQs series correlates to their acidic groups and C8-C7 ethylene diamine Chelation
Bridge along with bulky dual halogenations.

Methods:
We tested dual lipophilic- acidic chelating FQs with a genuine potential of antiproliferative propensities
based on their dual DPPH- and NO- radicals scavenging biocapacities using cell based – and colorimetric assays vs.
respective reference agents as their molecular action mechanism.

Results:
In this work, 9 lipophilic-acid chelating FQs and their cyclized TriazoloFQs (TFQs) designed to bear 7-
dihaloanilino substituents with a special focus on dichlorosubstitutions have been prepared, characterized and screened
against breast T47D and MCF7, Pancreatic PANC1, colorectal HT29, cervical HELA, lung A375, skin A549, and
Leukaemia K562 cancer cell lines using sulforhodamine B colorimetric bioassay. Parameters including potency, toxicity,
and selectivity (potency/toxicity) have been reported along with DPPH- and NO- radicals’ scavenging propensities -
as their molecular action mechanism- in comparison to ascorbic acid and indomethacin, respectively. Using Griess
assay in lipopolysaccharide (LPS) prompted RAW264.7 macrophages inflammation, IC50 values (μM) in the ascending
order of new FQs’ NO scavenging/antiinflammation capacity were 4a < 3a < 4c < indomethacin (23.8 <33.4 < 36 vs.
indomethacin’s 124, respectively). Exceptionally unlike the rest, reduced FQ, 4b exhibited remarkably superior DPPH
radical scavenging capacity to ascorbic acid (IC50 values (μM) 19.9 vs. 123.9, p < 0.001). In comparison to cisplatin;
nitroFQs (3a, 3b and 3c), the reduced FQs (4a, 4b, and 4c) and the TFQs (5a, 5b and 5c) exerted substantial micromolar
antiproliferation IC50 values < 50 μM in cervical Hela cancer cells but lacked comparable bioactivity in leukaemia
K562. In both breast MCF7 and T47D cancer cell lines, FQs/TFQs 4a < 3a < 5b (respective IC50 values (μM) 0.52 <
22.7 < 24 vs. cisplatin’s 41.8 and 0.03 < 4.8 < 27 vs. cisplatin’s 509), and in both GI system colorectal HT29 and pancreatic
PANC1 cancer cells FQs/TFQs 4a < 3a < 5b and 4a< 3a (respective IC50 values (μM) 0.12 < 3.5 < 15.9 vs.
cisplatin’s 148 and 1.5 < 10.4 vs. cisplatin’s 25.5), exerted nanomolar-micromolar affinities of antiproliferation potencies
< 50μM. Besides in lung A375 cancer cells FQs/TFQs 4c < 4a < 3a and in skin A549 cancer cells 5c < 3c < 4a <
3a < 4c (respective IC50 values (μM) 0.07 < 3.2 < 10.3 vs. cisplatin’s 390 and 0.5 < 2.3 < 3.8 < 8.8 < 17.3 vs. cisplatin’s
107) exhibited nanomolar-micromolar antineoplastic capacities < 50 μM. Their spectrum of selectivity indices for
safety in fibroblasts PDL-based 72h incubations was reported. Unequivocally 4b reduction of viability effectiveness
linked with its DPPH radical scavenging effects (without a matching antiinflammation effect). Explicitly 4a, 3a and 4c
exerted exquisite antiinflammation-selective cytotoxicity duality in vitro.

Conclusions:
Such a new potential chelation mechanism can explain the pronounced difference in antineoplastic activity
of new FQs/TFQs.