Synthesis, antimicrobial, antioxidant, cytotoxic, antiurease and molecular docking studies of N-(3-trifluoromethyl)benzoyl-N'-aryl thiourea derivatives

Aneela Maalik; Hina Rahim; Muhammad Saleem; Nighat Fatima; Abdur Rauf; Abdul Wadood; Muhammad Imran Malik; Ayaz Ahmed; Hummera Rafique; Muhammad Naveed Zafar; Muhammad Riaz; Lubna Rasheed; Amara Mumtaz

doi:10.1016/j.bioorg.2019.102946

Synthesis, antimicrobial, antioxidant, cytotoxic, antiurease and molecular docking studies of N-(3-trifluoromethyl)benzoyl-N'-aryl thiourea derivatives

Bioorg Chem. 2019 Jul:88:102946. doi: 10.1016/j.bioorg.2019.102946. Epub 2019 May 1.

Authors

Aneela Maalik¹, Hina Rahim², Muhammad Saleem³, Nighat Fatima⁴, Abdur Rauf⁵, Abdul Wadood⁵, Muhammad Imran Malik⁶, Ayaz Ahmed⁷, Hummera Rafique⁸, Muhammad Naveed Zafar⁹, Muhammad Riaz⁵, Lubna Rasheed¹⁰, Amara Mumtaz¹¹

Affiliations

¹ Department of Chemistry, COMSATS University Islamabad, Islamabad Campus, Park Road, Chak Shahzad, 45550 Islamabad, Pakistan. Electronic address: aneela.maalik@comsats.edu.pk.
² Department of Chemistry, COMSATS University, Abbottabad Campus, 22060 Abbottabad, Pakistan.
³ Department of Chemistry, University of Education, Lahore, Dera Ghazi Khan Campus, 32200 Punjab, Pakistan.
⁴ Department of Pharmacy, COMSATS University, Abbottabad Campus, 22060 Abbottabad, Pakistan.
⁵ Department of Chemistry, University of Swabi, 23561 Ambar, Khyber Pakhtunkhwa, Pakistan.
⁶ HEJ Research Institute of Chemistry, International Centre for Chemical and Biological Sciences, University of Karachi, 75270 Karachi, Pakistan.
⁷ Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Pakistan.
⁸ Department of Chemistry, University of Gujrat, 50700 Gujrat, Pakistan.
⁹ Department of Chemistry, Quaid-i-Azam University, Islamabad, Pakistan.
¹⁰ Department of Chemistry, University of Education, Township Campus, Lahore, Pakistan.
¹¹ Department of Chemistry, COMSATS University, Abbottabad Campus, 22060 Abbottabad, Pakistan. Electronic address: amaramumtaz@cuiatd.edu.pk.

PMID: 31054433
DOI: 10.1016/j.bioorg.2019.102946

Abstract

An irrefutable advancement has been noted for the infectious diseases caused due to ureolytic bacteria through the development of various drugs. Keeping in mind the extremely valuable synthetic utility and medicinal significance of thiourea derivatives, synthesis of new 3-trifluoromethyl benzoic acid thiourea derivatives (3a-j) were carried out. The biological potential of all compounds in terms of antimicrobial, antioxidant, cytotoxic and antiurease activities were studied. The compounds 3a, 3c and 3i with dichloro and methoxy groups substitution on the aryl group showed significant activity against all strain of bacteria while moderate to no activity was observed in remaining compounds. Whereas the antifungal evaluation showed that all compounds were active againts C. Albican and no activity was observed against C. Prapsilosis. The cytotoxic findings revealed the non-toxic nature of these compounds as IC₅₀ values of majority of the compounds are above 100 μm except for compounds 3f and 3g. In addition, these compounds exhibited better antioxidant potential as 100 μm concentration inhibited >50% reactive oxygen species (ROS) production except compounds 3e, 3f and 3j. The compound 3a proved to be the most potent urease inhibitor showing the highest enzyme % inhibition (93.1%) with IC₅₀ value of 8.17 ± 0.24 µM and found more active as compare to standard followed by compound 3e (92.6%), 3h (91.6%), 3d (90.8%), 3b (90.6%) and 3f (90.0%) with their respective IC₅₀ values. All the synthesized compounds were docked into the binding cavity of Urease (PDB ID: 4ubp). The most active compound 3a was also ranked as top on the docking score as it was found to show valuable interactions with the target protein along with good docking scores. Hence our results revealed that the synthesized compounds have potential to be used as potent urease inhibitors after further detailed mechanistic studies.

Keywords: Antimicrobial; Antiurease; Cytotoxic; MRSA; Molecular docking; Oxidative burst assay; Thiourea.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Antifungal Agents / chemical synthesis
Antifungal Agents / chemistry
Antifungal Agents / pharmacology*
Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Antioxidants / chemical synthesis
Antioxidants / chemistry
Antioxidants / pharmacology*
Bacteria / drug effects
Candida / drug effects
Cell Line, Tumor
Cell Proliferation / drug effects
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Mice
Microbial Sensitivity Tests
Molecular Docking Simulation*
Molecular Structure
NIH 3T3 Cells
Oxidative Stress / drug effects
Thiourea / analogs & derivatives
Thiourea / chemistry
Thiourea / pharmacology*
Urease / antagonists & inhibitors
Urease / metabolism

Substances

Anti-Bacterial Agents
Antifungal Agents
Antineoplastic Agents
Antioxidants
Enzyme Inhibitors
Urease
Thiourea