br Funding The research for this paper is conducted as

Funding The research for this paper is conducted as part of a PhD thesis at Pasteur Institute of Iran and it was financially supported by Pasteur Institute of Iran and the Iranian Centre for Communicable Diseases.
Conflict of interest
Acknowledgments
Introduction The viral enzyme integrase (IN), which mediates integration of the viral cDNA into the host genome by catalytic reactions-first catalyzes removal of the terminal dinucleotide from each 3′-end of the viral DNA (3′-processing) and subsequently medicates joining of the 3′-end of the viral DNA to the host DNA (strand transfer) during the viral replication cycle.1, 2 Because of lack of a cellular homologue and its essential role in viral replication, it is an attractive target for the development of new anti-HIV-1 inhibitors with high selectivity and low toxicity.3, 4 In the past two decades, IN-targeted antiviral research has led to the identification of various inhibitor types, of which the most prominent scaffolds feature is a diketo N1-Methylguanosine-5'-Triphosphate (DKA) structure or its heterocyclic bioisosteres.5, 6, 7, 8, 9 The dihydroxypyrimidine carboxamide derived from the evolution of DKA is a potent, reversible, and selective HIV-1 integrase strand transfer inhibitor. Extensive research on these chemotypes culminated with raltegravir11, 12 (Fig. 1), it is the first drug approved for clinical use target to HIV integrase. The pharmacophoric center 5-hydroxypyrimidone carboxamide could bind to divalent metal ions (Mg2+ or Mn2+) to block the strand transfer (ST) in the HIV-1 integrase catalytic site. Unfortunately, continuous mutation of viral genome leads to multi-drug resistant viral strains that are no longer susceptible to current therapy including raltegravir.13, 14, 15 The polyhydroxylated aromatics were also the first HIV integrase inhibitor identified, but the early polyhydroxylated derivatives were later demonstrated to inhibit viral entry or to be too toxic to be pursued as therapeutic IN inhibitors.16, 17 In order to study possible interaction between the two main classes of inhibitors (polyphenols and DKAs), a kind of catechol or dicaffeoyltartaric–DKA hybrids have been designed and tested as IN inhibitors following the goals of refining the pharmacophore, enhancing antiviral potency and improving cellular membranes permeability.18, 19 The majority of the hybrid compounds exhibited submicromolar potency against strand transfer and modest antiviral activities, thus, there is a clear need to optimize the structure of compounds into the highly potent inhibitory activity derivatives to HIV integrase. Despite the high interest generated by these compounds, little number of the compounds results in a lake of structure–activity relationships information for the class of inhibitors. In our previous studies, a series of polyhydroxylated aromatics were designed and synthesized as potential HIV-1 integrase inhibitors and evaluated their inhibitory activity to the strand transfer process of HIV-1 integrase.17, 20 On the basis of the consideration as well as on our interest in development of new anti-IN agents, we planned to explore the effect of polyhydroxylated aromatics and dihydroxypyrimidine hybrids to gain new insight in the fundamental structural requirements for anti-IN activity. Keeping in mind the pharmacophoric groups of hydroxypyrimidone carboxamide and polyhydroxylated aromatics, adjusting length of carbon chain of linker between two pharmacophoric group, we designed and synthesized compound 3,4,5-polyhydroxy-N-(3-(4-(5-methoxy-1-methyl-2-(4-substituted benzyl)-6-oxo-1,6-dihydropyrimidine-4-carbonyl)piperazin-1-yl)alkyl)benzamide (Fig. 2).
Results and discussion
Conclusion
Experimental section
Acknowledgments The authors would like to acknowledge financial support from the National Science Foundation of China (21272020), the Project of Construction of Innovative Teams and Teacher Career Development for Universities and Colleges under Beijing Municipality (IDHT20140504).