A Review of the Development of Multitarget Molecules against HIV-TB Coinfection Pathogens

Abstract

The human immunodeficiency virus (HIV) produces the pathologic basis of acquired immunodeficiency syndrome (AIDS). An increase in the viral load in the body leads to a decline in the number of T lymphocytes, compromising the patient's immune system. Some opportunistic diseases may result, such as tuberculosis (TB), which is the most common in seropositive patients. Long-term treatment is required for HIV-TB coinfection, and cocktails of drugs for both diseases are used concomitantly. The most challenging aspects of treatment are the occurrence of drug interactions, overlapping toxicity, no adherence to treatment and cases of resistance. Recent approaches have involved using molecules that can act synergistically on two or more distinct targets. The development of multitarget molecules could overcome the disadvantages of the therapies used to treat HIV-TB coinfection. This report is the first review on using molecules with activities against HIV and Mycobacterium tuberculosis (MTB) for molecular hybridization and multitarget strategies. Here, we discuss the importance and development of multiple targets as a means of improving adherence to therapy in cases of the coexistence of these pathologies. In this context, several studies on the development of structural entities to treat HIV-TB simultaneously are discussed.

Keywords: AIDS; HIV; coinfection; hybrid; multitarget; tuberculosis.

Figure 1

HIV replication cycle.

Figure 2

Chemical structure of the main antiretroviral drugs currently used in AIDS therapy.

Figure 3

Chemical structures of anti-TB drugs.

Figure 4

Classification of hybrids based their structure according to Morphy and Rankovic, adapted from [71].

Figure 5

Chemical structure of Canolide A (1) and its anti-HIV-1 profile.

Figure 6

Structural requirements for pyranocoumarins to exert anti-TB and anti-HIV activity [77].

Figure 7

Anti-HIV and anti-MTB activity of d4T-derived Compounds 2a–d, synthesized by Sriram et al. in 2004 [79].

Figure 8

Biological activity (anti-HIV cells: MSC/anti-MTB cells: H₃₇Rv) and stability of AZT derivatives synthesized by Sriram et al. in 2005 [80].

Figure 9

Anti-HIV (in CEM cells) and anti-MTB (in H37Rv cells) activity of the compounds synthesized by Sriram et al. in 2005 [81].

Figure 10

Anti-HIV and anti-MTB activities of isatin-thiosemicarbazone derivatives 5–7 [82,83,84,85,86,87,88].

Figure 11

Basic skeleton of the novel isatin derivatives 8–12 and their anti-HIV and anti-MTB activities [83,84,86,89].

Figure 12

Results of anti-HIV activity (CEM cells), inhibition of the HIV-1 integrase enzyme and anti-MTB activity of Compound 13, derived from tetracycline and fluoroquinolone [91].

Figure 13

Anti-HIV and anti-MTB activities of NFV-derived compounds [92].

Figure 14

Anti-HIV and anti-MTB activities of EFV derivatives 15a–d [93].

Figure 15

Biological activities (anti-HIV cells: MT-4/anti-MTB cells: H₃₇Rv) of the derivatives 16a–h synthesized by Senthilkumar and collaborators in 2009 [94].

Figure 16

Compounds 17a–d and their anti-HIV and anti-MTB activities reported by Senthilkumar and collaborators in 2009 [94].

Figure 17

Anti-HIV and anti-MTB activities of borrelidin reported by Bhikshapathi et al. in 2010 [95].

Figure 18

Chemical structure of the gallium nanoparticle (Ga-NP) 19 (tetraphenyl porphyrin of Ga).

Figure 19

Potential multitarget HIV-TB 20 reported by Vasu Nair et al. in 2015 [101].

Figure 20

The anti-HIV and anti-MTB activities of Compounds 22 and 23 [102].

Figure 21

Anti-HIV and anti-MTB activities, as well as cytotoxicity studies, of 3,5-bis(furan-2-ylmethylidene)-piperidin-4-substituted imines derivatives 24–27 [105].

Figure 22

Compounds 28 and 29 and their anti-HIV and anti-MTB activities reported by Chitre and collaborators in 2009 [113].

Figure 23

Niclosamide 30 is a potential dual anti-MTB and anti-HIV drug [74].