Noncovalent Sulfur Interactions in Medicinal Chemistry (Issue 7)
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By Jin Li
Like a halogen bond, it can be seen from the front and side view of the thiophene ring that a region of positive, σ-hole-like potential exists near the sulfur atom (Figure 1). [1] The presence of σ-hole on a sulfur atom is available for interaction with electron-donating atoms, particularly nitrogen and oxygen. For instance, most commonly sulfur-containing heterocycles can participate in attractive nonbonding interactions that are proving to be useful in the control of molecular conformation. As illustrated in Figure 1, there is a sulfur-long pair interaction in 2-(2’-thienyl)pyridine which causes “s-cis-locked” conformational preference. One of the earliest examples of an intramolecular N-S interaction that stabilized a specific conformation was reported in 1976. The small molecule single X-ray structure of compound 92 revealed a syn, coplanar arrangement of the electron-donating guanidine N atom and the acceptor S atom of the thiadiazole ring. [2]
A single replacement of the oxygen atom in compound 93 with a sulfur atom in compound 94 increased both Aurora A and Aurora B inhibition by at least 300-fold (Figure 2). Modeling of the heterocyclic core of compound 94 suggested that the two heterocyclic rings adopted a coplanar conformation in which the thiazole sulfur atom and the quinazoline N-3 atom were oriented proximal to each other. [3]
It was interesting to observe that a basic nitrogen atom in heteroaryl rings ortho- to the 2-amino group in compound 95 increased KDR inhibition by at least 30-fold, compared to isomer 97 with a meta-nitrogen. A single replacement of the sulfur atom in compound 95 with the oxygen atom in compound 96 decreased inhibition by at least 260-fold. Both two observations indicated that there was a key intramolecular interaction between the sulfur atom and nitrogen atom in compound 95, constraining binding favored conformation (Figure 2). [4]
There was 70-fold difference in potency between compounds 98 and 99, although both compounds had binding favored conformation resulting from intramolecular hydrogen bond and S-N interaction respectively. Calculations suggested that the difference in potency was more a function of desolvation costs, which are higher for the more basic compound 98 (Figure 2). [5]
In order to discover highly selective PI3K inhibitors based on primary hit compound 100, replacing amide moiety in compound 100 with pyridine moiety in compound 101 maintained the same desired conformation. The co-crystal structure of compound 101 in PI3K revealed that the pyridine ring was coplanar with the thiazole and with the nitrogen of the pyridine pointing inward. It was interpreted that long pair-sulfur interaction stabilized this conformation (Figure 3). [6]
As revealed above, intramolecular interaction between the sulfur atom in thiazole or fused-thiazole rings and adjacent nitrogen or oxygen plays a critical role in locking favored conformation. Thiazole or fused-thiazole building blocks are of great value (Figure 4).
An intramolecular O-S interaction plays a role in orienting the thiazolopyridine heterocycle of the factor Xa inhibitor Edoxaben (102), which was approved for the prevention of venous thromboembolism following lower-limb surgery. In the crystal structure of the structurally related factor Xa inhibitor 103, the close contact between the thiazole S and adjacent amide carbonyl O atom was considered to contribute to the correct alignment of the whole molecule (Figure 5). [7] Thiazole-2-carboxylic acid building blocks are of great value for the incorporation of O-S interaction into the molecule.
Compound 105 is a potent inhibitor of SIRT family members with IC50 values of 15 nM, 10 nM and 33 nM respectively, while the analogous compound 104 is about 10-fold weaker. These data are consistent with the co-crystal structure of SIRT3 with an analogue. The orientation of the 2-carboxamide is coplanar with the thienyl ring such that the oxygen atom lies proximal to the sulfur atom to facilitate a 1,4-electrostatic interaction. This topology facilitates four hydrogen bond interactions between the amide moiety and elements of the protein and a structural bridging water molecule (Figure 6). [8]
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An X-ray co-crystal structure of compound 107 confirmed that the key enzyme-inhibitor interaction was preserved as the topology of the carboxamide moiety favored by close O-S interaction. The importance of this interaction on biological activity was understood by the dramatic difference in potency that was observed between compound 107 and close isomer compound 106, with the latter 1500-fold weaker than the former. This was attributed to the distortion of the carboxamide moiety of compound 106 from planarity, which resulted in a poor alignment of the important hydrogen bond with the protein (Figure 7). [9]
References
[1] Brett R. Beno; et al. A survey of the role of noncovalent sulfur interactions in drug design. J. Med. Chem. 2015, 58, 4383-4438.
[2] Akiba K.; et al. Chemistry of hypervalent sulfur. V. A 13C-NMR study of the 1:1 adduct of “Hector’s base” with aryl cyanamides. Evidence for intramolecular S-N interaction. Tetrahedron Lett. 1976, 17, 3819-3820.
[3] Jung F. H.; et al. Discovery of novel and potent thiazoloquinazolines as selective Aurora A and B kinase inhibitors. J. Med. Chem. 2006, 49, 955-970.
[4] Bilodeau M. T.; et al. The discovery of N-(1,3-thiazol-2-yl)pyridine-2-amines as potent inhibitors of KDR kinase. Bioorg. Med. Chem. Lett. 2004, 14, 2941-2945.
[5] Park H.; et al. Discovery of picomolar ABL kinase inhibitors equipotent for wild type and T315I mutant via structure-based de novo design. J. Am. Chem. Soc. 2013, 135, 8227-8237.
[6] Matthew W. D. Perry; et al. Discovery of AZD8154, a dual PI3K inhibitor for the treatment of asthma. J. Med. Chem. 2021, 64, 8053-8075.
[7] Yoshikawa K.; et al. Design, synthesis, and SAR of cis-1,2-diaminocyclohexane derivatives as potent factor Xa inhibitors. Part II: exploration of 6-6 fused rings as alternative S1 moieties. Bioorg. Med. Chem. 2009, 17, 8221-8233.
[8] Disch J. S.; et al. Discovery of thieno[3,2-d]pyrimidine-6-carboxamides as potent inhibitors of SIRT1, SIRT2 and SIRT3. J. Med. Chem. 2013, 56, 3666-3679.
[9] Zhao L.; et al. Design, synthesis and SAR of thienopyridines as potent CHK1 inhibitors. Bioorg. Med. Chem. Lett. 2010, 20, 7216-8221.
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