Synthesis, anti-HIV activity, molecular modeling study and QSAR of new designed 2-(2-arylidenehydrazinyl)-4-arylthiazoles Amna Rauf a , Muhammad K. Kashif a , Bahjat A. Saeed b , Najim A. Al-Masoudi c, *, 1 , Shahid Hameed a, ** a Department of Chemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan b Department of Chemistry, College of Education for Pure Sciences, University of Basrah, Basrah, Iraq c Department of Chemistry, College of Science, University of Basrah, Basrah, Iraq article info Article history: Received 2 June 2019 Received in revised form 28 July 2019 Accepted 28 July 2019 Available online 31 July 2019 Keywords: Anti-HIV activity Arylthiazoles Cytotoxicity Molecular docking study QSAR abstract Taking into consideration the eminence of 1,3-thiazoles in medicinal chemistry and in a view of pro- curing more pronounced biological contour, the synthesis of 2-(2-arylidenehydrazinyl)-4-arylthiazoles 6 e43 was made possible by the cyclization reaction of thiosemicarbazones and a-bromoacetophenones. The thiosemicarbazones 5a-m were in turn synthesized from substituted benzaldehydes or acetophe- nones and thiosemicarbazide. Optimization of the reaction conditions was carried out in order to attain the target molecules in good yields. All the new compounds were evaluated in vitro for their antiviral activity against the replication of HIV-1 and HIV-2 in MT4 cells using a MTT assay. Screening results indicated that compounds 32e34 are the only compounds in the series inhibiting HIV-1 and HIV-2 replication in cell cultures with IC 50 of >2.71, >2.19 and > 1.71 mM, respectively. The molecular docking of compounds 32 and 34 with some amino acids of human immunodeficiency virus reverse transcriptase (HIV RT) were also studied. The preliminary quantum structure-activity relationship (QSAR) among the newly synthesized congeners was obtained by two methods, Multiple Linear Regression (MRL) and Genetic Function Approximation (GFA). © 2019 Published by Elsevier B.V. 1. Introduction Thiazoles have exhibited a broad spectrum of pharmacological activities as drugs for the treatment of a large number of diseases including viral [1], tumor [2e5], tubercular [6], alzheimer's [7], diabetes [8], leukemia [9], microbial [10], HIV, HCV, HAV and HSV [11 , 12]. Some of the approved drugs having thiazole backbone are dasatinib (anticancer) [13], ritonavir (anti-HIV-1) [14](1 , Fig. 1), nizatidine (anti-ulcer) [15] and fentiazac (anti-inflammatory) [16]. In addition, numerous 1,3-thiazole analogues exhibit remarkable anti-HIV activity [17e19](e.g: 2, IC 50 HIV RT ¼ 0.016 nM, Fig. 1)[20], besides many other pharmacological activities such as anti-cancer [21 ,22], urokinase inhibitors [23], anti-allergic [24], anti-oxidant [25], anti-inflammatory [26], analgesic [27], and anti-convulsant [28]. Thiazole-containing drug molecules are currently being used in the treatment of various central nervous system disorders [29]. Recently, Chimenti et al. [30] reported the synthesis and pharma- cological activity of cyclopentylidene-[4-(4 0 -chlorophenyl)thiazol- 2-yl]hydrazine (CPTH2, 3, Fig. 1) as a selective inhibitor of histone acetyltransferase Gcn5P (HAT), both in vitro and in vivo (IC 50 ¼ 0.80 mM). Deregulated HAT and histone deacetylase (HDAC) activity plays a role in the development of a range of cancers. Consequently, inhibitors of these enzymes have potential as anti- cancer agents. Considering the pharmacological significance of thiazole de- rivatives and in continuation of our attempts to develop new potent HIV-1 NNRTIs [31e35] herein we report the synthesis of a new series of 2-(2-arylidenehydrazinyl)-4-arylthiazoles and their effi- cacy as anti-HIV agents together with the quantum structure- activity relationship (QSAR) and molecular docking studies. * Corresponding author. ** Corresponding author. E-mail addresses: najim.al-masoudi@gmx.de (N.A. Al-Masoudi), shameed@qau. edu.pk (S. Hameed). URL: http://www.al-masoudi.de 1 Present address: Am Tannenhof 8, 78464 Konstanz, Germany. Contents lists available at ScienceDirect Journal of Molecular Structure journal homepage: http://www.elsevier.com/locate/molstruc https://doi.org/10.1016/j.molstruc.2019.07.113 0022-2860/© 2019 Published by Elsevier B.V. Journal of Molecular Structure 1198 (2019) 126866