Crocus sativus L. (family: Iridaceae) has been documented in traditional medicine with numerous medicinal properties. Recently, we have shown that C. sativus extract (IIIM-141) displays promising efficacy in a genetic mice (5XFAD) model of Alzheimer’s disease (AD) (ACS Chem. Neurosci. 2017, 16, 1756). To translate the available traditional knowledge and the scientifically validated results into modern medicine, herein we aimed to carry out its preclinical development. IIIM-141 is primarily a mixture of crocins containing trans-4-GG-crocin (36 % w/w) as the principal component. The in vitro studies show that IIIM-141 has protective as well as therapeutic properties in assays related to AD. It induces the expression of P-gp, thereby enhancing the amyloid-β clearance from an AD brain. It also inhibits NLRP3 inflammasome and protects SH-SY5Y cells against amyloid-β- and glutamate-induced neurotoxicities. In behavioral models, it decreased the streptozotocin-induced memory impairment in rats and recovered the scopolamine-induced memory deficit in Swiss albino mice at 100 mg/kg dose. The acute oral toxicity study shows that IIIM-141 is safe up to the dose of 2000 mg/kg, with no effect on the body weight and on the biochemical/hematological parameters of the rats. The repeated oral administration of IIIM-141 for 28 days at 100 mg/kg dose did not cause any preterminal deaths and abnormalities in Wistar rats. The pharmacokinetic analysis indicated that after oral administration of IIIM-141, the majority of crocin gets hydrolyzed to its aglycone crocetin. The sustained release (SR) capsule formulation was developed, which showed an improved in vitro dissolution profile and a significantly enhanced plasma exposure in the pharmacokinetic study. The SR formulation resulted in 3.3-fold enhancement in the area under the curve of crocetin and doubling of the crocetin/crocin ratio in plasma compared with the extract. The data presented herein will serve as the benchmark for further research on this botanical candidate.

Exploration of microbes isolated from north western Himalayas for bioactive natural products. A strain of Trichoderma lixii (IIIM-B4) was isolated from Bacopa monnieri L. The ITS based rDNA gene sequence of strain IIIM-B4 displayed 99% sequence similarity with different Trichoderma harzianum species complex. The highest score was displayed for Hypocrea lixii strain FJ462763 followed by H. nigricans strain NBRC31285, Trichoderma lixii strain CBS 110080, T. afroharzianum strain CBS124620 and Trichoderma guizhouense BPI:GJS 08135 respectively. Position of T. lixii (IIIM-B4) in phylogenetic tree suggested separate identity of the strain. Microbial dynamics of T. lixii (IIIM-B4) was investigated for small peptides. Medium to long chain length peptaibols of 11 residue (Group A), 14 residue (Group B) and 17 residue (Group C) were identified using Matrix Assisted Laser Desorption/Ionization-Time of Flight (MALDI-TOF) mass spectrometer. Optimization is undeniably a desideratum for maximized production of desirable metabolites from microbial strain. Here optimization studies were carried out on T. lixii (IIIM-B4) using different growth media through Intact Cell Mass Spectrometry (ICMS). A multifold increase was obtained in production of 11 residue peptaibols using rose bengal medium. Out of these, one of them named as Tribacopin AV was isolated and sequenced through mass studied. It was found novel as having unique sequence Ac-Gly-Leu-Leu-Leu-Ala-Leu-Pro-Leu-Aib-Val-Gln-OH. It was found to have antifungal activity against Candida albicans (25 μg/mL MIC). In this study, we isolated a strain of T. lixii (IIIM-B4) producing medium and long chain peptaibols. One of them named as Tribacopin AV was found novel as having unique sequence Ac-Gly-Leu-Leu-Leu-Ala-Leu-Pro-Leu-Aib-Val-Gln-OH, which had antifungal properties.

As part of our endeavor to enhance survival of natural product derived drug candidates and to guide the medicinal chemist to design higher probability space for success in the anti cancer drug development area, we embarked on a detailed study of the property space for a collection of natural product derived anti cancer molecules. We carried out a comprehensive analysis of properties for 24 natural products derived anti cancer drugs including clinical development candidates and a set of 27 natural products derived anti cancer lead compounds. In particular, we focused on understanding the interplay among eight physicochemical properties including like partition coefficient (log P), distribution coefficient at pH=7.4 (log D), topological polar surface area (TPSA), molecular weight (MW), aqueous solubility (log S), number of hydrogen bond acceptors (HBA), number of hydrogen bond donors (HBD) and number of rotatable bonds (n_Rot) crucial for drug design and relationships between physicochemical properties, ADME (absorption, distribution, metabolism, and elimination) attributes, and in silico toxicity profile for these two sets of compounds. This analysis provides guidance for the chemist to modify the existing natural product scaffold or designing of new anti cancer molecules in a property space with increased probability of success and may lead to the identification of druglike candidates with favorable safety profiles that can successfully test hypotheses in the clinic.

Highly efficient catalyst free methods for the synthesis of α-hydroxy-β-oxophosphonates and α-oxoesters have been described. The existence of a 2-oxo group in α-oxoaldehydes is a key factor in promoting the reaction of the tervalent phosphite form towards 2-oxoaldehydes in the synthesis of α-hydroxy-β-oxophosphonates. The in situ activated α-C–H atom of α-hydroxy-β-oxophosphonates sustains aerobic intramolecular nucleophilic displacement in a curious way to produce α-oxoester.