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Innovative Medicines & Omics Synthesis and docking of diorganotin (IV) chelates

hydrogen bonding features. Overall, ligands 1 and 2 appear indicating a gradual increase in their potential to permeate
highly favorable for further development, while ligands the skin across the series. Despite this trend, all values
3 and 4, though structurally promising, may require remain within the range, indicating moderate to low
additional formulation or optimization efforts due to their skin permeability. Overall, while the compounds show
higher lipophilicity. strong oral absorption profiles, caution is warranted due
In drug discovery, several ADME-related parameters to their CYP inhibition profiles and P-gp substrate status,
are crucial for assessing a compound’s pharmacokinetic particularly for L-3 and L-4. These factors may influence
profile. Gastrointestinal absorption reflects the ability of both efficacy and safety during drug development,
a drug to be absorbed through the digestive tract, which requiring further ADME profiling and possible structural
is crucial in achieving effective oral bioavailability. BBB refinement to mitigate risks.
permeability determines whether a compound can cross In several cases, increased steric hindrance may prevent
into the central nervous system; while this is desirable hydrolysis or metabolic degradation, allowing the complex
for central nervous system (CNS)-targeted drugs, it may to reach the target intact and potentially increasing its
be avoided in non-CNS drugs to reduce neurological side selectivity or prolonging its activity. Bulkier groups
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effects. The status of a compound as a P-glycoprotein (P-gp) generally increase lipophilicity, which may enhance
substrate influences its distribution and bioavailability, as membrane permeability, potentially increasing bioactivity
P-gp actively transports substances out of cells, potentially in lipophilic environments (e.g., tumor cell membranes).
lowering intracellular drug concentrations. Steric hindrance around the Sn (IV) center often increases
According to the in-silico ADME analysis, all four kinetic stability by physically blocking access to reactive
ligands presented in Table 8 exhibit high gastrointestinal sites. This can protect against ligand exchange, hydrolysis,
absorption, implying good oral bioavailability potential. or oxidation, which is especially important in physiological
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However, none of the ligands are predicted to be BBB environments (aqueous, neutral pH). Moreover, Schiff
permeant, suggesting limited potential for central nervous base-derived diorganotin (IV) complexes with bulky
system activity, which may be advantageous in reducing substituents (e.g., Ph SnL vs. Me SnL) exhibited a greater
2
2
neurological side effects for non-CNS targets. Notably, antimalarial and antioxidant activity. 40
the L-1 and L-2 are not substrates of P-gp, implying 4. Conclusion
lower chances of efflux-related bioavailability reduction.
In contrast, L-3 and L-4 are identified as P-gp substrates, In the present work, sterically hindered 4-(2’mercapto-
which may lead to reduced intracellular concentrations phenyl-iminoalkyl/aroyl)-2,4-dihydro-5-methyl-2-
due to active efflux, particularly in the intestine or BBB phenyl-3H-pyrazol-3-ones ligands were employed for
regions. the synthesis of organotin complexes under the specified
reaction conditions. Molecular docking studies revealed
The inhibition of cytochrome P450 (CYP) enzymes,
such as CYP1A2, CYP2C19, CYP2C9, CYP2D6, and the extensive interactions of ligands with key active-
site residues of proteins. These findings suggest that
CYP3A4, can lead to significant drug–drug interactions
(DDIs) by affecting the metabolism of co-administered L-4 possesses strong potential as a broad-spectrum
therapies. Notably, CYP3A4 metabolizes a large proportion antibacterial agent. In contrast, ligands L-1 and L-3 showed
moderate binding affinities, with occasional performance
of clinically used drugs. All four ligands are predicted comparable to the reference ligands, while L-2 consistently
to inhibit multiple major cytochrome P450 enzymes,
namely CYP2C19, CYP2C9, CYP2D6, and CYP3A4, exhibited the weakest binding across all targets.
while the first two ligands additionally show inhibition DFT calculations suggest that all four chelates display
of CYP1A2 (Table 8). Such broad-spectrum inhibition similar electronic properties with only slight variations.
suggests a high potential for DDIs, which could complicate Among them, Chelate-4 is the most reactive, characterized
co-administration with other medications metabolized by the smallest energy gap, highest electron affinity, and
by these enzymes. Skin permeability, measured as log K , greatest softness, indicating enhanced electron-accepting
p
estimates a compound’s ability to penetrate the skin; higher ability and chemical reactivity. In contrast, Chelate-1
negative values suggest lower transdermal absorption, shows the greatest stability with the widest energy gap.
which is important for evaluating the potential of dermal These subtle electronic differences suggest that while the
exposure or suitability for topical drug delivery. As shown in chelates share similar molecular frameworks, variations
Table 8, the skin permeability values (log K ) progressively in their reactivity could influence their interactions with
p
increase from ligand L-1 to L-4 (from −5.23 to −4.46 cm/s), biological targets. Although both L-3 and L-4 possess

Volume 2 Issue 3 (2025) 79 doi: 10.36922/IMO025140019