Table 1.

Investigational agents in visceral leishmaniasis

Reference	Active compound	In vitro efficacy	In vitro or Ex vivo toxicity	In vivo efficacy	Other characteristics
Mukherjee et al118	Imipramine, N-(c-dimethylaminopropyl)-iminodibenzyl HCl, a tricyclic antidepressant	IC50 and EC50 same in SSG(S) or SSG (R) L. donovani strains	60μM cleared 100% of intracellular parasites while 100% MO̵s remained viable upto 90 μM of imipramine	5 mg/kg/day for 4 weeks, cleared 99.5% parasites in SSG-R or SSG-S hamster	FDA approved oral drug ↓ IL 10 and TGFβ level ↑ TNF α, IFN γ and iNOS in imipramine treated infected hamsters
Palit et al119	Sertraline a selective serotonin reuptake inhibitor	IC50 against L. donovani promastigotes & amastigotes of 2.2 and 2.3 mg/L		10 mg/kg body weight, two times per week for 4 weeks orally ↓ed parasite load in spleen by 72%& in liver by 70% in BALB/c mice	Induces ↓ in cytoplasmic ATP levels & oxygen consumption rate in promastigotes suggesting the involvement of an apoptosis mode of cell death.
Suryawanshi et al120	Triazole integrated phenyl heteroterpenoids compound 3a	IC50-6.4 ± 1.2 μM in amastigotes of L. donovani 100% Inhibition at 40 μM	CC 50 - 112.4 ± 10.9 μM SI - 18	79 ± 11% inhibition of parasite multiplication at 50 mg/ kg × 5 days I.P. in hamster model.	Inhibits growth of Leishmania amastigotes by preventing the 14 a-demethylation of lanosterol and effectively blocking synthesis of ergosterol.
Sharma et al121	Quinazolinone-Triazine. 8a 8g	IC50–against promastigote ± amastigotes - 7.05 ± 2.3 μM ± 3.95 ± 2.3 μM IC50 against promastigotes ± amastigotes - ±40 μM ± 4.39 ±1.4 μM	CC50 > 400 SI >101.26 CC50 > 400 SI >91.1	73.15 ± 12.69% inhibition of parasite 80.93 ± 10.50%. against L.donovani in hamster model
Kyriazis et al122	Olive tree extracts Oleuropein Hydroxytyrosol	Oleuropein – IC50-110±32 in amastigotes Hydroxytyrosol- IC50-38.7±3 in amastigotes	Oleuropein CC50 -356±23 SI 3.24 Hydroxytyrosol - CC50 180±16 SI 4.65	14 alternate day IP oleuropein reduced spleen parasitic burden >80% at 3 days & >95% in liver and spleen at 6weeks post treatment in BALB/c mice
Bhattacharya et al123	Bungarus caeruleus snake venom (BCV)	IC50 - L. donovani promastigote - 14.5 μg/ml Amastigote - 11.2 μg/ml.		20μg/kg and 40μg/kg body ↓parasite count by 54.9% andj 74.2% in spleen and 41.4% and 60.4% in liver of infected BALB/c mice.	Increased production of TNF-α, IFN- γ, ROS, NO in infected mice.
Khaliq et al124	peganine hydrochloride. Peganum harmala seeds	L. donovani promastigotes IC50 38 (±1.23) μg/ ml. In intracellular Amastigotes IC50 μg/ml	Devoid of cytotoxic effect in J774A.1 macrophages	In-vivo activity, 79.6 (+/−8.07)% ± 87.5 ±9.10)% f inhibition of parasites in hamsters at a oral dose of 100mg/kg & 200mg/kg for 5 days respectively.	Causes apoptosis-like cell death due to L. donovani's topoisomerase I inhibition
Maes et al125 Germonprez et al126	Maesabalide III triterpenoid saponins, from plant Maesa balansae	IC50 value 7 ng/ml in L. infantum amastigotes	CC50 > 32μg/mL in human fibroblast (MRC-5) cell line	Single dose of MB-III at 0.8 mg/kg causes 94.2% reduction of the liver amastigote burden in hamsters	Efficacy comparable to that of a single dose of liposomal amphotericin B at 5 mg/kg
Mittra et al127	luteolin flavonoids	IC50 value 12.5μM in L.donovani promastigotes 12.5 μM reduced the intracellular parasite load by 70% in L. Donovani-infected BALB/c mice peritoneal macrophages	No effect on normal human T-cell blasts.	A dose of 3.5-mg/kg twice a week for 1month reduced the splenic parasite load by over 80% in hamsters	Inhibited DNA synthesis in promastigotes, and promoted topoisomerase-II mediated linearization of kDNA minicircles.
Zhai et al128	oxygenated chalcones 35m4ac 24m4ac	IC50 value −0.81 ± 0.3 IC50 value −0.65 ± 0.35μM in L.donovani amastigotes		20mg/kg for 6 days ↓ in parasite load in liver 97% 88%	Interferes with the function of the parasite mitochondria
Chen et al129	licochalcone A			20 mg/kg per day i.p. for 6 days resulted in a > 96% ↓ in parasite load in the liver and the spleen 5to 150 mg/kg oral for 6days resulted in >65 and 85% ↓ in the parasite load in liver and spleen
Medda et al130	Amarogentin, a secoiridoid glycoside from Indian medicinal plant Swertia chirata		blood pathology, histological staining of tissues and liver enzyme levels showed no toxicity.	2.5 mg/kg of amarogentin, in 0.5 mL niosomal suspension s.c. every 3 days for a total of 6 doses ↓ 9o% parasite load in spleen in hamsters	Inhibit the activity of DNA-topoisomerase I of L. donovani.

SSG-S -antimony sensitive SSG-R- antimony resistant

MO̵ - peritoneal exudate cells of BALB/c mice

IC 50- half maximum inhibitory concentration

CC 50, half maximum cytotoxic con- centration

SI -Selectivity index -The selectivity index (SI) is defined as the ratio of CC 50 on Vero cells to IC 50 on L. donovani intramacrophagic amastigotes.

I.P.- intraperitoneal

ROS, reactive oxygen species; NO, nitric oxide;