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Despite the undoubted success in the development of human immunodeficiency virus type 1 (HIV-1) therapy by means of a bundle of reverse transcriptase (RT), integrase (IN), protease, viral entry and fusion inhibitors, this infection still remains a significant health threat. One of the current problems associated with HIV therapy is phosphorolytic excision of 3’-terminal nucleotide analogs (e.g. AZT, 3TC) and the emergence of drug-resistant virus variants containing specific RT mutations called thymidine analogue mutations (TAMs, M41L, D67N, K70R, T215Y, K219Q), which enhance pyrophosphorolytic excision of NRTIs. Herein, we synthesized methylenebisphosphonates 40 BPs, several of which simultaneously inhibited phosphorolytic activity of native and drug-resistant forms of HIV-1 RT, RT-catalyzed elongation and two enzymatic activities of the integrase. In addition BPs exhibited low anti-RNase H activity. For effective inhibition, BPs should be comprised of three elements: (i) the Mg2+-coordinating methylene bisphosphonate backbone, (ii) the aromatic halogenated pharmacophore linked to the backbone through (iii) the inert aliphatic linker. The most active was a bis-dichlorophenyl containing bisphosphonate 47, that suppressed RT and IN at low micromolar concentrations. Some compounds didn’t suppress double mutant RT bearing K103N and Y181C. These mutations are associated with resistance to non-nucleoside RT inhibitors (NNTRIs). BP 47 was active against the three RT variants: the wild type, double mutant and RT bearing thymidine analogue mutations. 47 appeared to be a non-competitive inhibitor of RT-catalyzed elongation. Thus, the BPs are multitarget inhibitors of HIV-1 RT catalyzed pyrophosphorolysis and elongation and HIV-1 IN catalyzed 3’-processing and strand transfer.