a-g). a benzyl substituted hydroxyl group (fig. 4 h) improves metal-chelating capability (compared to structure j in fig. 4) while a methoxy group (i) is much less potent due to steric clash by the additional methyl group with the catalytic metals. when researching diketo derivates, the central pyrrole ring of structure k in fig. 4 was replaced by a series of aromatic systems having various substitution patterns. that provided optimum relative orientation of the benzyl and diketoacid (dka) site chain. structure l in fig. 4 resulted in 100 fold increase in potency. benard et al (2004) synthesized inis with a quinoline subunit and an ancillary aromatic ring linked by functionalized spacers such as amide, hydrazide, urea and hydroxyprop-1-en-3-one moiety. they found that the amide group containing derivatives were the most promising ones. by synthesizing series of styrylquinones researchers found out that a carboxyl group at c-7, a hydroxylgroup at c-8 in the quinoline subunit and an ancillary phenyl ring (figure 4: structure m) are required for inhibition, although alterations of the ring are tolerated. two hydroxyl groups on the ancillary phenyl ring are also required for inhibitory potency. pharmacophore figure 5: binding of dkas to dde amino acid residues of integrase since critical structure information is scarce on hiv integrase catalysis it is difficult to find the exact pharmacophore for its inhibition. wang et al (2010) hoped that by studying the sar and pharmacophore of a dual inhibitor scaffold, focusing both on integrase and reverse transcriptase (rt) it would be possible to observe anti-integrase activity. by studying the sar of hiv integrase inhibitors it was possible to find that for optimal integrase inhibition the pharmacophore requires a regiospecific (n-1) dka of a specific length. a dka functionality or its heterocyclic bioisostere that selectively inhibit strand transfer seem to be present in all major chemotypes of integrase inhibitors. as detailed in the sar discussion above the two necessary structural components of ini are a benzyl hydrophobic moiety and a chelating triad to bind the mg2+ ions. for the triad to bind the mg2+ ions has to be ionized (see fig. 5) and thus a pharmacophore bioisostere has to be ionized too and the benzyl pharmacophore bioisostere must to be very hydrophobic. however, despite previous success in clinical development (raltegravir), a detailed binding model is lacking so it has proven difficult to structure base the design of integrase inhibitors. when the pharmacophore of salicylic acid and catechol were merged, new chemical scaffolds were created. the adjacent hydroxyl and carboxylic groups on salicylic acid could bind with the metal ions and serve as their pharmacophore. polyhydroxylated aromatic inhibitors are mostly active against strand transfer reactions and 3‘-processing which suggests a mechanism that targets both steps. this is a very important part of the compound as it can be used to bind to the divalent metal on the active site of in and as such be effective against viral strains that are resistant to strand transfer specific inhibitors. resistance it has been discovered that over 60 variations of insti mutations cause in vivo and in vitro resistance. due to these mutations and development of resistance the inhibitors are less effective against the virus. resistance of ini corresponds to those of other arv drugs. first in resistance is caused by primary mutations that decrease ini sensitivity in combination with secondary mutations that further reduce virus sensitivity and/or repair decreased fitness of the virus. secondly there is a genetic barrier to ini resistance, defined by the number of mutations required for the loss of clinical ini activity. thirdly there is extensive but incomplete cross-resistance among the inis. a loop containing amino acid residues 140–149 is located in the catalytic-core domain and is important for in function as mentioned before. this loop is flexible and even though its role is not quite known it is thought to be important and its functions critical for dna binding. this resistance appears within mutations in this in-coding region. the resistance to raltegravir and elvitegravir is primarily due to the same two mutation pathways but other primary mutations are also involved for each of the drugs. some mutations increase resistance to the drugs to a large extent than others. for example, one of the most common mutation pathway increases the resistance to raltegravir up to 100 times more than the second most common one. resistance to integrase inhibitor s/gsk1349572 is still being developed and the resistance has not been fully characterized. when it was assessed alongside the primary mutations of raltegravir and elvitegravir it did not show cross-resistance which means that it could be useful against drug resistant viruses. raltegravir has limited intestinal absorption and thus resistance cannot be overcome by prescribing higher doses. newer drugs are warranted to overcome this pharmacological disadvantage and gain plasma concentrations high enough to target raltegravir-resistant viruses. current status figure 6: structure of mk-2048 with important pharmacophore highlighted the search for new ways to improve treatment of patients infected with hiv is constant. considering the experience that has been gathered since the 1980s of arv drug development arrival of instis as a new potent class of arv signals a new era in the treatment of hiv. development of a successful insti treatment was accomplished when raltegravir was discovered by merck sharp & dohme limited. a conditional marketing authorization was licensed in december 2007 by the european commission which was valid throughout the european union. in 2009 this authorization was converted to a full marketing authorization and in the same year the fda changed the approval from accelerated to traditional approval and listed the drug as a first line arv treatment agent. the second insti drug, elvitegravir, was identified by japan tobacco and clinical trials began in 2005. in 2011 the drug was still in phase three clinical trials, where it is being compared to raltegravir, in treatment experienced subjects and is also in phase two development in naïve subjects as a part of a multidrug treatment. s/gsk1349572 is an integrase inhibitor discovered by viiv/shinongi which was entering phase three in clinical trials in 2011. this new drug is promising and seems to be well tolerated and so far shows better results than both raltegravir and elvitegravir. since there have been problems with resistance to raltegravir and elvitegravir, scientists have started to work on new second generation integrase inhibitors, such as mk-2048 which in 2009 was developed by merck. it's a prototype second generation insti that remains potent against viruses containing mutations against raltegravir and elvitegravir. the mechanism of action and sar of mk-2048 is the same as of the other instis, the structure of mk-2048 shown in figure 6 with essential pharmacophore highlighted. even though drugs discussed above are promising the development has a long way to go and many things are still unknown about the efficacy, safety and mechanism of action of these drugs.