Synthesis, biological evaluation, and docking studies of novel pyrrolo[2,3-b]pyridine derivatives as both ectonucleotide pyrophosphatase/phosphodiesterase inhibitors and antiproliferative agents

Ullah, Saif; El‐Gamal, Mohammed I.; El-Gamal, Randa; Pelletier, Julie; Sévigny, Jean; Shehata, Mahmoud K.; Anbar, Hanan S.; Iqbal, Jamshed

doi:10.1016/j.ejmech.2021.113339

Cited by 15 publications

(11 citation statements)

References 47 publications

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“…The effect of synthesized molecules on the activity of isozymes ENPP1 and ENPP3 was evaluated by using the previously reported method with minor changes. , Initial screening of the compounds was performed at 100 μM concentration per well in triplicate in the buffer: 5 mM MgCl 2 , 0.1 mM ZnCl 2 , and 50 mM Tris–HCl, adjusted to pH 9.5–9.6. Briefly, 30 ng ENPP1 and 32 ng ENPP3 proteins per well were added followed by the addition of 100 μM synthesized compounds dissolved in 10% dimethyl sulfoxide (DMSO).…”

Section: Methodsmentioning

confidence: 99%

“…Several structures with sulphonate moiety are reported to possess therapeutic importance such as suramin (Figure ) with a complex structure and poly sulphonate groups, being widely used as a positive control of choice in different biological studies . In the previous study, we have reported pyrrolo[2,3- b ]pyridine derivatives such as ( N -(pyrrolo[2,3- b ]pyridine-1-carbonyl)benzenesulfonamide), which was found as a selective inhibitor of ENPP1 with an IC 50 value of 4.50 ± 0.16 μM and carbohydrazide-based derivative, which selectively blocked the activity of ENPP3 to half of the maximal value of 0.15 μM. , Various previously reported structures with sulphonate scaffolds including raloxifene sulphonates, benzofuran, and benzothiophene sulphonates exhibited significant enzyme inhibitory activity to sub-micromolar levels, for example, raloxifene sulphonate derivative 3-(4-(2-(piperidin-1-yl)ethoxy)benzoyl)-2-(4-(tosyloxy)phenyl)benzo[ b ]thiophen-6-yl-4-methylbenzenesulfonate tabulated selective inhibition of isozyme ENPP1 to an IC 50 value of 0.45 μM, and benzothiophene derivative (4-(benzo[ b ]thiophen-5-yl)phenyl cyclohexanesulfonate) was endowed with IC 50 = 0.12 μM against ENPP1 and 1.89 μM toward ENPP3. , We have also reported sulphonate derivatives mainly based on non-aromatic or saturated cyclic hydrocarbons. These structures exhibited considerable inhibitory activity but limited preferable selectivity among the three isozymes ENPP1, ENPP2, and ENPP3 …”

Section: Introductionmentioning

confidence: 99%

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Synthesis and Biological Evaluation of Arylamide Sulphonate Derivatives as Ectonucleotide Pyrophosphatase/Phosphodiesterase-1 and -3 Inhibitors

et al. 2022

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Aberrant level of ectonucleotide pyrophosphatase/phosphodiesterase-1 and -3 is linked with numerous disorders, for instance, diabetes, cancer, osteoarthritis, chondrocalcinosis, and allergic reactions. These disorders may be cured or minimized by blocking the activity of ENPP1 and ENPP3 isozymes. In this study, arylamide sulphonates were synthesized, characterized, and evaluated for their capability to affect the activity of isozymes ENPP1 and ENPP3. Among the selective inhibitors of ENPP1, compounds 4f and 4q exhibited sub-micromolar IC 50 values of 0.28 ± 0.08 and 0.37 ± 0.03 μM, respectively, followed by 7a , with IC 50 equal to 0.81 ± 0.05 μM, whereas out of the selective inhibitors of isozyme ENPP3, 4t and 7d preferably lessened the activity to half of the maximal inhibitory concentration of 0.15 ± 0.04 and 0.16 ± 0.01 μM alternatively. In addition, many structures including 4c , 4g , 4k , 4l , 4n , 4o , 4r , 4s , 7b , 7c , and 7e inhibited the activity of both isozymes to a significant level. Enzyme kinetic study of compound 4j revealed an uncompetitive mode of inhibition of ENPP1 isozyme, while 7e competitively blocked the activity of ENPP3. Cell viability analysis revealed the compound 4o as a cytotoxic agent against MCF7 (human breast cancer cell line) with a percentage inhibition of 63.2 ± 2.51%, whereas compounds 4c , 4d , 4n , and 7d decreased the HeLa cell viability (human cervical cancer cell line) to more than 50%. The tested compounds were non-cytotoxic against HEK293 (a human embryonic kidney cell line). Molecular docking analysis of selected inhibitors of both isozymes produced optimistic interactions with the influential amino acids, such as Leu290, Lys295, Tyr340, Asp376, His380, and Pro323 of ENPP1, whereas residues Asn226, His329, Leu239, Tyr289, Pro272, Tyr320, and Ala205 of ENPP3 crystallographic structure formed interactions with the potent inhibitors.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of Arylamide Sulphonate Derivatives as Ectonucleotide Pyrophosphatase/Phosphodiesterase-1 and -3 Inhibitors

et al. 2022

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“…Pyridine ring plays a role in the formation of a discontinuous silver film on a polymer composite using its derivative poly (4‐vinyl pyridine) P4VP. Due to its beneficial and extensive biological properties, pyridine derivatives are used in the treatment of various diseases such as cancer, diabetes, hyperpigmentation, tuberculosis, hyperplasia and ulcers 1‐8 …”

Section: Introductionmentioning

confidence: 99%

Quantum chemical, spectroscopic and molecular docking investigations of potential pulmonary fibrosis drug methyl 2‐chloro 4‐iodonicotinate

Pandimeena¹,

Mathavan²,

Samuel

et al. 2022

J of Molecular Recognition

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In this work, the methyl 2-chloro 4-iodonicotinate (MCIN) was investigated to study the structural, spectroscopic and electronic properties using density functional theory (DFT) quantum chemical calculations. The most stable structure of MCIN was optimized by DFT/B3LYP method with a LanLD2Z basis set. The optimized parameters and vibrational wavenumbers were determined. The vibrational task of the molecule was done by potential energy distribution calculations. The 13 C NMR spectrum of the MCIN molecule was simulated by the Gauge-Invariant-Atomic Orbital method using a dimethyl sulfoxide solution and the isotropic chemical shift values of the molecule were calculated and observed. Ultraviolet-visible spectra were simulated and observed. The pharmaceutical activity was predicted using frontier molecular orbital and natural bond orbital analysis. The reactive sites of the MCIN molecule were determined using Mulliken atomic charge distribution, molecular electrostatic potential surface and the local reactivity analysis. The molecular docking analysis confirms that the title molecule can be used in drug design for the treatment of pulmonary fibrosis.

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“…Nitrogen-, oxygen- and sulfur-based heterocyclic compounds are contributing extensively in the current medicinal chemistry because of their wide applications in drug discovery and development [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ]. As the potentially privileged scaffolds, pyridine-fused heterocycles have attracted attention due to their effective and widespread biological properties for the treatment of different diseases such as cancer, diabetes, hyperpigmentation, tuberculosis, hyperplasia and ulcer [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Pyridine Scaffolds, Phenols and Derivatives of Azo Moiety: Current Therapeutic Perspectives

et al. 2021

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Synthetic heterocyclic compounds have incredible potential against different diseases; pyridines, phenolic compounds and the derivatives of azo moiety have shown excellent antimicrobial, antiviral, antidiabetic, anti-melanogenic, anti-ulcer, anticancer, anti-mycobacterial, anti-inflammatory, DNA binding and chemosensing activities. In the present review, the above-mentioned activities of the nitrogen-containing heterocyclic compounds (pyridines), hydroxyl (phenols) and azo derivatives are discussed with reference to the minimum inhibitory concentration and structure–activity relationship, which clearly indicate that the presence of nitrogen in the phenyl ring; in addition, the hydroxyl substituent and the incorporation of a diazo group is crucial for the improved efficacies of the compounds in probing different diseases. The comparison was made with the reported drugs and new synthetic derivatives that showed recent therapeutic perspectives made in the last five years.

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Synthesis, biological evaluation, and docking studies of novel pyrrolo[2,3-b]pyridine derivatives as both ectonucleotide pyrophosphatase/phosphodiesterase inhibitors and antiproliferative agents

Cited by 15 publications

References 47 publications

Synthesis and Biological Evaluation of Arylamide Sulphonate Derivatives as Ectonucleotide Pyrophosphatase/Phosphodiesterase-1 and -3 Inhibitors

Synthesis and Biological Evaluation of Arylamide Sulphonate Derivatives as Ectonucleotide Pyrophosphatase/Phosphodiesterase-1 and -3 Inhibitors

Quantum chemical, spectroscopic and molecular docking investigations of potential pulmonary fibrosis drug methyl 2‐chloro 4‐iodonicotinate

Pyridine Scaffolds, Phenols and Derivatives of Azo Moiety: Current Therapeutic Perspectives

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