Discovery of novel phthalimide analogs: Synthesis, antimicrobial and antitubercular screening with molecular docking studies

Heba S Rateb; Hany E A Ahmed; Sahar Ahmed; Saleh Ihmaid; Tarek H Afifi

doi:10.17179/excli2016-654

Discovery of novel phthalimide analogs: Synthesis, antimicrobial and antitubercular screening with molecular docking studies

EXCLI J. 2016 Dec 6:15:781-796. doi: 10.17179/excli2016-654. eCollection 2016.

Authors

Heba S Rateb¹, Hany E A Ahmed², Sahar Ahmed³, Saleh Ihmaid⁴, Tarek H Afifi⁵

Affiliations

¹ Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah 30001, Saudi Arabia; Department of Pharmaceutical and Medicinal Chemistry, Pharmacy College, Misr University for Science and Technology, Cairo, Egypt.
² Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah 30001, Saudi Arabia; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Cairo 11884, Egypt.
³ Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah 30001, Saudi Arabia; Medicinal Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
⁴ Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah 30001, Saudi Arabia.
⁵ Chemistry Department, Faculty of Science, Taibah University, 30002, Al-Madinah Al-Munawarah, Saudi Arabia.

Abstract

In continuation of our endeavor towards the design and development of potent and effective antimicrobial agents, three series of phthalimide derivatives (4a-i, 5a-f, and 6a-c) were synthesized, fully characterized and evaluated for their potential antibacterial, antifungal and antimycobacterial activities. These efforts led to the discovery of nine compounds 4c, 4f, 4g, 4h, 4i, 5c, 5d, 5e, and 6c (MIC range from 0.49 to 31.5 μg/mL) with potent antibacterial, antifungal, and antimycobacterial activities. Ampicillin, ciprofloxacin, amphotericin B were used as references for antibacterial and antifungal screening respectively, while isoniazid was used as a reference for antimycobacterial testing. Furthermore, molecular modeling studies were done to explore the binding mode of the most active derivatives to M. tuberculosis enoyl reductase (InhA) and DNA gyrase B. Our study showed the importance of both hydrogen bonding and hydrophobic interactions as a key interaction with the target enzymes.

Keywords: antitubercular agents; docking; phthalimide; structure-activity relationships.