The difficulty of developing an efficient malaria vaccine along with increasing spread of multidrug resistant strain of Plasmodium falciparum to the available antimalarial drugs poses the need to discover safe and efficacious antimalarial drugs to control malaria. An alternative strategy is to synthesize compounds possessing structures similar to the active natural products or marketed drugs. Several biologically active natural products and drugs contain β-carboline moiety. In the present study, few selected β-carboline derivatives have been synthesized and tested for their in vitro and in vivo antiplasmodial activity against the rodent malaria parasite Plasmodium berghei (NK-65). The designed analogs exhibited considerable in vitro antimalarial activity. Two compounds (1R,3S)-methyl 1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate (9a) and (1R,3S)-methyl 1-(pyridin-3-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate (9b) were further selected for in vivo studies. Both the lead compounds (9a and 9b) were observed to be safe for oral administration. The therapeutic effective dose (ED50) for 9a and 9b were determined and in the animal model, 9a (at 50 mg/kg dose) exhibited better activity in terms of parasite clearance and enhancement of host survival. Biochemical investigations also point toward the safety of the compound to the hepatic and renal functions of the rodent host. Further studies are underway to explore its activity alone as well as in combination therapy with artesunate against the human malaria parasite P. falciparum.

Increasing resistance to presently available antimalarial drugs urges the need to look for new promising compounds. The β-carboline moiety, present in several biologically active natural products and drugs, is an important scaffold for antimalarial drug discovery. The present study explores the antimalarial activity of a β-carboline derivative (1 R ,3 S )-methyl 1-(benzo[ d ][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1 H -pyrido[3,4- b ]indole-3-carboxylate ( 9a ) alone in vitro against Plasmodium falciparum and in vivo in combination therapy with the standard drug artesunate against Plasmodium berghei . Compound 9a inhibited both 3D7 and RKL-9 strains of P. falciparum with half-maximal inhibitory concentration (IC 50 ) < 1 μg/mL, respectively. The compound was nontoxic (50% cytotoxic concentration (CC 50 ) > 640 μg/mL) to normal dermal fibroblasts. Selectivity index was >10 against both the strains. The compound exhibited considerable in vivo antimalarial activity (median effective dose (ED 50 ) = 27.74 mg/kg) in monotherapy. The combination of 9a (100 mg/kg) and artesunate (50 mg/kg) resulted in 99.69% chemosuppression on day 5 along with a mean survival time of 25.8 ± 4.91 days with complete parasite clearance. Biochemical studies indicated the safety of the HIT compound to hepatic and renal functions of mice. Molecular docking also highlighted the suitability of 9a as a potential antimalarial candidate.

Background Incidence of pulmonary aspergillosis is rising worldwide, owing to an increased population of immunocompromised patients. Notable potential of the pulmonary route has been witnessed in antifungal delivery due to distinct advantages of direct lung targeting and first-pass evasion. The current research reports biomimetic surface-active lipid-polymer hybrid (LPH) nanoparticles (NPs) of voriconazole, employing lung-specific lipid, i.e., dipalmitoylphosphatidylcholine and natural biodegradable polymer, i.e., chitosan, to augment its pulmonary deposition and retention, following nebulization. Results The developed nanosystem exhibited a particle size in the range of 228–255 nm and drug entrapment of 45–54.8%. Nebulized microdroplet characterization of NPs dispersion revealed a mean diameter of  ≤ 5 μm, corroborating its deep lung deposition potential as determined by next-generation impactor studies. Biophysical interaction of LPH NPs with lipid-monolayers indicated their surface-active potential and ease of intercalation into the pulmonary surfactant membrane at the air-lung interface. Cellular viability and uptake studies demonstrated their cytocompatibility and time-and concentration-dependent uptake in lung-epithelial A549 and Calu-3 cells with clathrin-mediated internalization. Transepithelial electrical resistance experiments established their ability to penetrate tight airway Calu-3 monolayers. Antifungal studies on laboratory strains and clinical isolates depicted their superior efficacy against Aspergillus species. Pharmacokinetic studies revealed nearly 5-, 4- and threefolds enhancement in lung AUC, Tmax, and MRT values, construing significant drug access and retention in lungs. Conclusions Nebulized LPH NPs were observed as a promising solution to provide effective and safe therapy for the management of pulmonary aspergillosis infection with improved patient compliance and avoidance of systemic side-effects.

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