Original article Nonclassical antifolates, part 4. 5-(2-Aminothiazol-4-yl)-4-phenyl-4H- 1,2,4-triazole-3-thiols as a new class of DHFR inhibitors: Synthesis, biological evaluation and molecular modeling study q Ghada S. Hassan a, b , Shahenda M. El-Messery c , Fatmah A.M. Al-Omary a , Sarah T. Al-Rashood a , Marwa I. Shabayek d , Yasmin S. Abulfadl d , El-Sayed E. Habib e , Salwa M. El-Hallouty f , Walid Fayad f , Khaled M. Mohamed f , Bassem S. El-Menshawi g , Hussein I. El-Subbagh h, * a Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia b Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt c Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, P.O. Box 35516, Mansoura, Egypt d Department of Pharmacology (Biochemistry Section), Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University, 12311 Cairo, Egypt e Department of Pharmaceutics and Pharmaceutical Technology (Microbiology), College of Pharmacy, Taibah University, Almadinah Almunawwarah, 344, Saudi Arabia f Drug Bioassay-Cell Culture Laboratory, Department of Pharmacognosy, Pharmaceutical and Drug Industries Division, National Research Center, Dokki, Giza 12622, Egypt g Department of Pharmacognosy, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University,12311 Cairo, Egypt h Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences & Pharmaceutical Industries, Future University,12311 Cairo, Egypt article info Article history: Received 28 February 2013 Received in revised form 19 May 2013 Accepted 25 May 2013 Available online 4 June 2013 Keywords: Synthesis Substituted thiazoles DHFR inhibitors Molecular modeling study abstract A new series of compounds possessing 5-(2-aminothiazol-4-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol skeleton was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, antitumor and schistosomicidal activities. Four active compounds were allocated, the antibacterial 22 (comparable to gentamicin and ciprofloxacin), the schistosomicidal 29 (comparable to praziquantel), the DHFR inhibitor 34 (IC 50 0.03 mM, 2.7 fold more active than MTX), and the antitumor 36 (comparable to doxorubicin). Molecular modeling studies concluded that recognition with key amino acid Leu4 and Val1 is essential for DHFR binding. Flexible alignment and surface mapping revealed that the obtained model could be useful for the development of new class of DHFR inhibitors. Ó 2013 Elsevier Masson SAS. All rights reserved. 1. Introduction Dihydrofolate reductase (DHFR) is one of the key enzymes in the process of DNA replication, it catalyzes the transformation of 7,8- dihydrofolate into tetrahydrofolate [1]. The latter serves as a necessary cofactor in the important one-carbon transfer reactions involved in the pyrimidine, purine, and amino acid biosynthetic pathways. The lower levels of tetrahydrofolate result in decreased conversion of glycine to serine, reduced methionine synthesis, and lower thymidylate levels, with a subsequent arrest of DNA repli- cation [2,3]. DHFR has a proven record as a drug target in the treatment of bacterial, parasitic infections and cancer chemo- therapy [4,5]. Numerous studies showed that the structure of the classical DHFR inhibitor methotrexate (MTX) can be modified considerably while significant inhibitory potency still retained [6,7]. Parasitic diseases are one of the causes of mortality and morbidity worldwide. The WHO estimates that one billion people are affected by parasitic infections, such as malaria, leishmaniasis, trypanosomiasis and schistosomiasis. The annual mortality asso- ciated with parasitic infections, is estimated 500,000 deaths [8]. The majority of the drugs used to treat these diseases is old and has several limitations, including high cost, poor efficacy, and toxicity [9]. Moreover, the development of drug resistance makes the q For parts 1e3 see Refs. [24e26]. * Corresponding author. Tel./fax: þ20 2 26186111. E-mail address: subbagh@yahoo.com (H.I. El-Subbagh). Contents lists available at SciVerse ScienceDirect European Journal of Medicinal Chemistry journal homepage: http://www.elsevier.com/locate/ejmech 0223-5234/$ e see front matter Ó 2013 Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.ejmech.2013.05.039 European Journal of Medicinal Chemistry 66 (2013) 135e145