Synthesis of New 3-Heteroarylindoles as Potential Anticancer Agents
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Biological Screening (Cytotoxic Activity)
2.3. Examination of the Compound Activities Leads to the Following Conclusions
- The activities of the synthesized compounds depend on the structural skeleton and electronic environment of the molecules.
- Based on our limited study, the 1,3,4-thiadiazole ring as in 27 has in vitro inhibitory activity greater than the 1,3-thiazole ring in 12 and more than the triazolopyridopyrimidine ring in 19.
2.3.1. For the 1,3-Thiazole Ring 12a–c,e
- The in vitro inhibitory activity of the 4-methylthiazole is greater than 4-phenylthiazole (12a > 12e). This may be due to the positive inductive effect (+I effect) of the methyl group (increase activity) or the steric effect caused by phenyl group (decrease activity).
- The introduction of electron-donating group (methyl) at C4 of the phenyl group at position 4 in the 1,3-thiazole ring enhances the antitumor activity. In contrast, introduction of an electron-withdrawing group (chlorine) decreases the antitumor activity (12b > 12a > 12c).
2.3.2. For Triazolopyridopyrimidines 19a–c,e–i
- For substituent at position 3: the ester group (CO2Et) gives higher activity than the amide group (CONHPh) or the acetyl group (Ac) (19e > 19i > 19a).
- Generally, on fixing the substituents at position 3, the electron-donating group (methyl or methoxy) at C4 of the phenyl ring enhances the antitumor activity while the electron-withdrawing group (chlorine) decreases the antitumor activity (19b > 19a > 19c and 19g > 19f > 19e > 19h).
2.3.3. For 1,3,4-Thiadiazoles 27a–c
- The in vitro inhibitory activity of compounds with substituents at position 5 are in the order of: COOEt > CONHPh > CH3CO (27b > 27c > 27a).
3. Experimental
3.1. Chemistry
3.1.1. Synthesis of 3-(1H-Indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (5)
3.1.2. Synthesis of Thiones (7a,b)
3.1.3. Synthesis of 2-(3-(1H-Indol-3-yl)-5-(p-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-substituted-5-(aryl diazenyl)thiazole (12a–e)
3.1.4. Alternate Synthesis of 12e
Coupling of Thiazole 15e with Benzenediazonium Chloride
3.1.5. General Procedure for the Reaction of Hydrazonoyl Halides 8 with Thiones 7a,b
3.1.6. Alternate Synthesis of 19a,e,i
3.1.7. Synthesis of N’-(1-(1H-Indol-3-yl)ethylidene)-2-cyanoacetohydrazide (22)
3.1.8. Synthesis of 3-(2-(1-(1H-Indol-3-yl)ethylidene)hydrazinyl)-2-cyano-3-oxo-N-phenylpropane thioamide (25)
3.1.9. Reaction of 25 with Hydrazonoyl Chlorides 8a,e,i
3.2. Antitumor Activity Assay
4. Conclusions
Acknowledgments
Author Contributions
Conflicts of Interest
References
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- Sample Availability: Samples of the synthsized compounds are available from the authors.
Compound No. | R | Ar | IC50 (µM) |
---|---|---|---|
12a | CH3 | Ph | 4.92 |
12b | CH3 | 4-MeC6H4 | 0.95 |
12c | CH3 | 4-ClC6H4 | 14.52 |
12e | Ph | Ph | 19.44 |
19a | CH3CO | Ph | 6.88 |
19b | CH3CO | 4-MeC6H4 | 4.68 |
19c | CH3CO | 4-ClC6H4 | 69.85 |
19e | CH3CH2OCO | Ph | 4.83 |
19f | CH3CH2OCO | 4-MeC6H4 | 5.49 |
19g | CH3CH2OCO | 4-MeOC6H4 | 3.05 |
19h | CH3CH2OCO | 4-ClC6H4 | 18.61 |
19i | PhNHCO | Ph | 6.07 |
27a | CH3CO | Ph | 2.04 |
27b | CH3CH2OCO | Ph | 1.01 |
27c | PhNHCO | Ph | 1.27 |
Doxorubicin | - | - | 0.75 |
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Abdelhamid, A.O.; Gomha, S.M.; Abdelriheem, N.A.; Kandeel, S.M. Synthesis of New 3-Heteroarylindoles as Potential Anticancer Agents. Molecules 2016, 21, 929. https://doi.org/10.3390/molecules21070929
Abdelhamid AO, Gomha SM, Abdelriheem NA, Kandeel SM. Synthesis of New 3-Heteroarylindoles as Potential Anticancer Agents. Molecules. 2016; 21(7):929. https://doi.org/10.3390/molecules21070929
Chicago/Turabian StyleAbdelhamid, Abdou O., Sobhi M. Gomha, Nadia A. Abdelriheem, and Saher M. Kandeel. 2016. "Synthesis of New 3-Heteroarylindoles as Potential Anticancer Agents" Molecules 21, no. 7: 929. https://doi.org/10.3390/molecules21070929