Chikungunya virus (CHIKV) inhibitors from natural sources: a medicinal chemistry perspective

Abstract

Chikungunya virus (CHIKV) is one of the re-emerging "neglected" tropical diseases whose recent outbreak affected not only Africa and South-East Asia but also several parts of America and Europe. To date, despite its serious nature, no antivirals or vaccines were developed in order to counter this resurgent infectious disease. The recent advancement in crystallography and availability of crystal structures of certain domains of CHIKV initiates the development of anti-CHIKV agents using structure-based drug design or synthetic medicinal chemistry approach. Despite the fact that almost 50% of the new chemical entities against several biological targets were either obtained from natural products or natural product analogues, a very humble effort was directed towards identification of novel CHIKV inhibitors from natural products. In this review, besides a brief overview on CHIKV as well as the nature as a source of medicines, we highlight the current progress and future steps towards the discovery of CHIKV inhibitors from natural products. This report could pave the road towards the design of novel semi-synthetic derivatives with enhanced anti-viral activities.

Fig. 1

a Countries and territories where chikungunya cases have been reported (highlighted in green as of November 18, 2014) and b cases of chikungunya outbreak during 1952–2006, the regions highlighted in ‘red’ have been reported with chikungunya outbreak during that period [3]

Fig. 2

Some example of natural products used in the treatment of several diseases. 2D structures of several natural product drugs used in the treatment of cancer (paclitaxel, a), hypertension (reserpine, b), malaria (artemisinin, c). Compound d [10] is one of the natural product which displayed inhibitory activity against neglected tropical disease, dengue virus infection

Fig. 3

Representation of CHIKV NSP2 (PDB: 3TRK [14]) which highlights the active site region of NSP2 (represented in green spheres, a as well as critical residues of active site are highlighted in orange (ball and stick representation, b)

Fig. 4

Structure of CHIKV NSP3 macrodomain in complexed with ADP ribose derivative (PDB: 3GPO [16], a). The active site residues interacting with NSP3 active site might act as a foot print to design novel chemical entities targeting CHIKV NSP3

Fig. 5

The mature glycoprotein complex of CHIKV (PDB: 3N42 [17]) which might act as a promising target to develop novel drug molecules targeting CHIKV structural proteins

Fig. 6

2D structural representation of tigliane-type diterpenoids trigowiin A (1) prostratin (2), phorbol (3), 12-O-tetradecanoylphorbol 13-acetate (TPA, 4), and 4α-TPA (5)

Fig. 7

Structural representation of anacolosine (6), octadeca-9,11,13-triynoic acid (7), (13E)-octadec-13-en-9,11-diynoic acid (8), (13E)-octadec-13-en-11-ynoic acid (9), lupenone (10), β-amyrone (11), and (S)-sambunigrin (12)

Fig. 8

2D structural representation of 12-O-decanoylphorbol-13-acetate (13) and 12-O-decanoyl-7-hydroperoxy-phorbol-5-ene-13-acetate (14) isolated from the leaves of Croton mauritianus. R3=R4=C₉H₁₉

Fig. 9

Structural representation of daphnane diterpenoid orthoesters isolated from Trigonostemon cherrieri

Fig. 10

Structural representation of harringtonine (21), a cephalotaxine alkaloid which displayed significant inhibitory activity against CHIKV [28]

Fig. 11

Chemical representation of compound 22 which displayed inhibitory activity against CHIKV NSP2 [29]

Fig. 12

2D structural representations of compound 23-26 which displayed antiviral activities against EGFP and Rluc marker genes expressed by the CHIKV [30]

Fig. 13

2D structural representation of daphnane diterpenoid orthoester based CHIKV inhibitor, trigocherrierin A (27) [31]

Fig. 14

Structural representation of a jatrophane ester (28) which exhibited selective inhibitory activity against CHIKV [32]. “R” represents tiglyloxy (Tig) group

Fig. 15

2D structural feature of epigallocatechin-3-gallate (29)

Fig. 16

Chemical representation of quinine (30), an antimalarial compound which displayed anti-CHIKV activity