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Molecular docking study and antiviral evaluation of 2-thioxo-benzo[g]quinazolin-4(3H)-one derivatives.

Al-Salahi R, Abuelizz HA, Ghabbour HA, El-Dib R, Marzouk M - Chem Cent J (2016)

Bottom Line: The cytotoxicity (CC50), effective concentration (EC50) and the selectivity index (SI) values were determined.Based on their EC50 values, a number of the investigated compounds demonstrated weak to moderate activity relative to their parents.Accordingly, compounds 5-9, 11, 15-18, 21, 22, 24, 25, 27 and 28 were active against CVB4, and compounds 5 and 24 were active against HSV-1 and 2 in comparison to ribavirin and acyclovir, which were used as reference drugs.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P. O. Box 2457, Riyadh, 11451 Saudi Arabia.

ABSTRACT

Background: The persistent appearance of viral strains that causes a resistant viral infection has led to continuous trials for the design and development of novel antiviral compounds. Benzoquinazoline compounds have been reported to exhibit an interesting antiviral activity. This work aims to study and evaluate the antiviral activity of a newly prepared 2-thioxo-benzo[g]quinazolin-4(3H)-one series against herpes simplex (HSV-1 & 2) and coxsackievirus (CVB4).

Methods: The antiviral activity was performed using the MTT assay, in which Vero cells (obtained from the American Type Culture Collection, ATCC) were propagated in fresh Dulbecco's Modified Eagle's Medium (DMEM) and challenged with 10(4) doses of the virus. Thereafter, the cultures were treated simultaneously with two-fold serial dilutions of the tested compound and incubated at 37 °C for 48 h. Molecular docking studies were done on the CVB4 2A proteinase enzyme using Molegro Virtual Docker software.

Results: The cytotoxicity (CC50), effective concentration (EC50) and the selectivity index (SI) values were determined. Based on their EC50 values, a number of the investigated compounds demonstrated weak to moderate activity relative to their parents. Accordingly, compounds 5-9, 11, 15-18, 21, 22, 24, 25, 27 and 28 were active against CVB4, and compounds 5 and 24 were active against HSV-1 and 2 in comparison to ribavirin and acyclovir, which were used as reference drugs.

Conclusion: The obtained results gave us some useful insights about the characteristic requirements for future trials to build up and design more active and selective antiviral 2-thioxo-benzo[g]quinazolin-4(3H)-one agents.Graphical abstractCompound 24 superimposed with Ribavirin in CV B4 2A Proteinase enzyme (PDB: 1Z8R) active site.

No MeSH data available.


Related in: MedlinePlus

Antiviral and cytotoxicity evaluation of the synthesized compounds 1–28 compared to ribavirin and acyclovir. a Cytotoxicity effect (CC50). b Antiviral evaluation against CVB4 (EC50). c Antiviral evaluation against HSV-2 (EC50). d Antiviral evaluation against HSV-1 (EC50). All the values represented in (μg/mL)
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Fig1: Antiviral and cytotoxicity evaluation of the synthesized compounds 1–28 compared to ribavirin and acyclovir. a Cytotoxicity effect (CC50). b Antiviral evaluation against CVB4 (EC50). c Antiviral evaluation against HSV-2 (EC50). d Antiviral evaluation against HSV-1 (EC50). All the values represented in (μg/mL)

Mentions: In outlining the results in Table 2 and Fig. 1, it should be clarified that modifications on the lead structures 1–3 afforded new structural features (5–28) with a wide range of effects against the HSV and CVB4 viruses. For instance, S-alkylated products 7–28 exhibited significant activity against Coxsackie B4. In particular, compounds 7–9, 11, 15–18, 21, 22, 24, 25, 27 and 28 were more active than their parents 1–3. Moreover, variations in the type of the N-alkyl and S-alkyl (heteroalkyl) groups resulted in variations of the activity, in which compound 9 represented against CVB4 as the most active among the S-alkylated compounds (SI = 5.57). Compounds 15, 21, 24 and 28 showed a pronounced activity against CVB4 (SI = 3.60, 3.73, 3.85 and 3.31, respectively). In regard to anti-herpes activity, compound 1 was inactive, but its S-alkylated products 7–15 exhibited slight activity. Similarly, the parents 2 and 3 appeared less active than their chemically transformed products 16–21 and 22–28, respectively. However, hydrazino products 5 and 6 offered more advantages in terms of activity against HSV and CVB4 viruses. Depending on the values of the SI-parameter, 5 gave rise to the greatest activity against HSV-1 (4.28), followed by HSV-2 (5.18) and CVB4 (6.27). Moreover, the presence of the butyl group at the “R” position provided a significant effect against CVB4 and HSV viruses. This effect can be seen in both S-alkylated and hydrazino derivatives. However, the “R1” position requires a hydrophobic moiety to provide a selective antiviral activity against CVB4, as in compound 9. On the other hand, compound 5 exhibited a non-specific antiviral activity against CVB4 and HSV viruses. This effect also can be seen with compound 24 that has a 3-cyanobenzyl moiety at “R1” position but with a phenyl group instead of butyl at “R” position.Fig. 1


Molecular docking study and antiviral evaluation of 2-thioxo-benzo[g]quinazolin-4(3H)-one derivatives.

Al-Salahi R, Abuelizz HA, Ghabbour HA, El-Dib R, Marzouk M - Chem Cent J (2016)

Antiviral and cytotoxicity evaluation of the synthesized compounds 1–28 compared to ribavirin and acyclovir. a Cytotoxicity effect (CC50). b Antiviral evaluation against CVB4 (EC50). c Antiviral evaluation against HSV-2 (EC50). d Antiviral evaluation against HSV-1 (EC50). All the values represented in (μg/mL)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4837545&req=5

Fig1: Antiviral and cytotoxicity evaluation of the synthesized compounds 1–28 compared to ribavirin and acyclovir. a Cytotoxicity effect (CC50). b Antiviral evaluation against CVB4 (EC50). c Antiviral evaluation against HSV-2 (EC50). d Antiviral evaluation against HSV-1 (EC50). All the values represented in (μg/mL)
Mentions: In outlining the results in Table 2 and Fig. 1, it should be clarified that modifications on the lead structures 1–3 afforded new structural features (5–28) with a wide range of effects against the HSV and CVB4 viruses. For instance, S-alkylated products 7–28 exhibited significant activity against Coxsackie B4. In particular, compounds 7–9, 11, 15–18, 21, 22, 24, 25, 27 and 28 were more active than their parents 1–3. Moreover, variations in the type of the N-alkyl and S-alkyl (heteroalkyl) groups resulted in variations of the activity, in which compound 9 represented against CVB4 as the most active among the S-alkylated compounds (SI = 5.57). Compounds 15, 21, 24 and 28 showed a pronounced activity against CVB4 (SI = 3.60, 3.73, 3.85 and 3.31, respectively). In regard to anti-herpes activity, compound 1 was inactive, but its S-alkylated products 7–15 exhibited slight activity. Similarly, the parents 2 and 3 appeared less active than their chemically transformed products 16–21 and 22–28, respectively. However, hydrazino products 5 and 6 offered more advantages in terms of activity against HSV and CVB4 viruses. Depending on the values of the SI-parameter, 5 gave rise to the greatest activity against HSV-1 (4.28), followed by HSV-2 (5.18) and CVB4 (6.27). Moreover, the presence of the butyl group at the “R” position provided a significant effect against CVB4 and HSV viruses. This effect can be seen in both S-alkylated and hydrazino derivatives. However, the “R1” position requires a hydrophobic moiety to provide a selective antiviral activity against CVB4, as in compound 9. On the other hand, compound 5 exhibited a non-specific antiviral activity against CVB4 and HSV viruses. This effect also can be seen with compound 24 that has a 3-cyanobenzyl moiety at “R1” position but with a phenyl group instead of butyl at “R” position.Fig. 1

Bottom Line: The cytotoxicity (CC50), effective concentration (EC50) and the selectivity index (SI) values were determined.Based on their EC50 values, a number of the investigated compounds demonstrated weak to moderate activity relative to their parents.Accordingly, compounds 5-9, 11, 15-18, 21, 22, 24, 25, 27 and 28 were active against CVB4, and compounds 5 and 24 were active against HSV-1 and 2 in comparison to ribavirin and acyclovir, which were used as reference drugs.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P. O. Box 2457, Riyadh, 11451 Saudi Arabia.

ABSTRACT

Background: The persistent appearance of viral strains that causes a resistant viral infection has led to continuous trials for the design and development of novel antiviral compounds. Benzoquinazoline compounds have been reported to exhibit an interesting antiviral activity. This work aims to study and evaluate the antiviral activity of a newly prepared 2-thioxo-benzo[g]quinazolin-4(3H)-one series against herpes simplex (HSV-1 & 2) and coxsackievirus (CVB4).

Methods: The antiviral activity was performed using the MTT assay, in which Vero cells (obtained from the American Type Culture Collection, ATCC) were propagated in fresh Dulbecco's Modified Eagle's Medium (DMEM) and challenged with 10(4) doses of the virus. Thereafter, the cultures were treated simultaneously with two-fold serial dilutions of the tested compound and incubated at 37 °C for 48 h. Molecular docking studies were done on the CVB4 2A proteinase enzyme using Molegro Virtual Docker software.

Results: The cytotoxicity (CC50), effective concentration (EC50) and the selectivity index (SI) values were determined. Based on their EC50 values, a number of the investigated compounds demonstrated weak to moderate activity relative to their parents. Accordingly, compounds 5-9, 11, 15-18, 21, 22, 24, 25, 27 and 28 were active against CVB4, and compounds 5 and 24 were active against HSV-1 and 2 in comparison to ribavirin and acyclovir, which were used as reference drugs.

Conclusion: The obtained results gave us some useful insights about the characteristic requirements for future trials to build up and design more active and selective antiviral 2-thioxo-benzo[g]quinazolin-4(3H)-one agents.Graphical abstractCompound 24 superimposed with Ribavirin in CV B4 2A Proteinase enzyme (PDB: 1Z8R) active site.

No MeSH data available.


Related in: MedlinePlus