Aman Mahajan

Synthetic medicinal chemistry of selected antimalarial natural products

Natural products remain a rich source of novel molecular scaffolds for novel antimalarial agents in the fight against malaria. This has been well demonstrated in the case of quinine and artemisinin both of which have served as templates for the development of structurally simpler analogues that either served or continue to serve as effective antimalarials. This review will expound on these two natural products as well as other selected natural products that have served either as antimalarial agents or as potential lead compounds in the development of antimalarial drugs.

Synthesis and in vitro antitubercular activity of ferrocene-based hydrazones

We report here the synthesis and in vitro antitubercular activity of a new series of ferrocenyl derivatives. The quinoline-ferrocene hybrid 5 exhibited significant activity (MIC=2.5-5 μg/ml) against Mycobacterium tuberculosis. Results indicate that such hybrid compounds provide an efficient approach for future pharmacological developments to fight against tuberculosis. Moreover, the antimalarial drug candidate ferroquine (FQ, SSR97193) was also evaluated mainly because of its structural similarity. FQ was found to display moderate inhibitory activity (MIC=10-15 μg/ml) against M. tuberculosis. This new drug may offer an interesting alternative in endemic area where malaria and tuberculosis coexist.

High-Resolution Crystal Structures of Drosophila melanogaster Angiotensin-Converting Enzyme in Complex with Novel Inhibitors and Antihypertensive Drugs

Angiotensin I-converting enzyme (ACE), one of the central components of the renin-angiotensin system, is a key therapeutic target for the treatment of hypertension and cardiovascular disorders. Human somatic ACE (sACE) has two homologous domains (N and C). The N- and C-domain catalytic sites have different activities toward various substrates. Moreover, some of the undesirable side effects of the currently available and widely used ACE inhibitors may arise from their targeting both domains leading to defects in other pathways. In addition, structural studies have shown that although both these domains have much in common at the inhibitor binding site, there are significant differences and these are greater at the peptide binding sites than regions distal to the active site. As a model system, we have used an ACE homologue from Drosophila melanogaster (AnCE, a single domain protein with ACE activity) to study ACE inhibitor binding. In an extensive study, we present high-resolution structures for native AnCE and in complex with six known antihypertensive drugs, a novel C-domain sACE specific inhibitor, lisW-S, and two sACE domain-specific phosphinic peptidyl inhibitors, RXPA380 and RXP407 (i.e., nine structures). These structures show detailed binding features of the inhibitors and highlight subtle changes in the orientation of side chains at different binding pockets in the active site in comparison with the active site of N- and C-domains of sACE. This study provides information about the structure-activity relationships that could be utilized for designing new inhibitors with improved domain selectivity for sACE.

Synthesis and evaluation of hybrid drugs for a potential HIV/AIDS-malaria combination therapy

Malaria and HIV are among the most important global health problems of our time and together are responsible for approximately 3 million deaths annually. These two diseases overlap in many regions of the world including sub-Saharan Africa, Southeast Asia and South America, leading to a higher risk of co-infection. In this study, we generated and characterized hybrid molecules to target Plasmodium falciparum and HIV simultaneously for a potential HIV/malaria combination therapy. Hybrid molecules were synthesized by the covalent fusion of azidothymidine (AZT) with dihydroartemisinin (DHA), a tetraoxane or a 4-aminoquinoline derivative; and the small library was tested for antiviral and antimalarial activity. Our data suggests that compound 7 is the most potent molecule in vitro, with antiplasmodial activity comparable to that of DHA (IC(50)=26 nM, SI>3000), a moderate activity against HIV (IC(50)=2.9 μM; SI>35) and not toxic to HeLa cells at concentrations used in the assay (CC(50)>100 μM). Pharmacokinetics studies further revealed that compound 7 is metabolically unstable and is cleaved via O-dealkylation. These studies account for the lack of in vivo efficacy of compound 7 against the CQ-sensitive Plasmodium berghei N strain in mice, when administered orally at 20mg/kg.

Synthesis and Antiplasmodial and Antimycobacterial Evaluation of New Nitroimidazole and Nitroimidazooxazine Derivatives

The synthesis and antiplasmodial and antimycobacterial evaluation of two new series of nitroimidazole and nitroimidazooxazine derivatives is described. The majority of these compounds, especially hybrids 9d, 9f, and 14b, exhibited potent activity against the chloroquine-resistant K1 strain of Plasmodium falciparum. Furthermore, a notable number from the tetrazole series were significantly more active against M. tuberculosis than kanamycin, a standard TB drug.

Meclonazepam analogues as potential new antihelmintic agents

New analogues of the potent antihelmintic meclonazepam were prepared and evaluated against Schistosoma mansoni. The biological data suggests substitution at positions 2 and 4 of meclonazepam could provide promising analogues for prophylactic and therapeutic activity against S. mansoni.

Effects of a domain-selective ACE inhibitor in a mouse model of chronic angiotensin II-dependent hypertension

The somatic isozyme of ACE (angiotensin I-converting enzyme) comprises two distinct zinc-dependent catalytic domains with different substrate specificities for angiotensin I (cleaved selectively by the C-domain) and bradykinin (cleaved equally efficiently by both the N- and C-domains). Classical ACEIs (ACE inhibitors) target both domains, with side effects such as cough and angio-oedema being attributed, in part, to N-domain inhibition, probably through bradykinin accumulation. We questioned whether a novel C-domain-selective ACEI (lisW-S) has anti-hypertensive effects without influencing bradykinin status. AngII (angiotensin II)-dependent hypertension was studied in mice that express active human renin in the liver (TtRhRen). Compared with wild-type littermates, TtRhRen mice displayed cardiac hypertrophy and had significantly elevated SBP [systolic BP (blood pressure)] as determined by tail cuff sphygmomanometry (150±3 compared with 112±5 mmHg; P<0.05) and telemetry (163±3 compared with 112±2 mmHg; P<0.01). Treatment with the non-selective ACEI lisinopril (1 mg/kg of body weight per day via an osmotic mini-pump for 2 weeks) reduced SBP (127±3 compared with. 154±6; P<0.05). Similarly, treatment with the C-domain selective ACEI lisW-S (lisinopril-tryptophan; 3.6 mg/kg of body weight per day via an osmotic mini-pump for 2 weeks) reduced BP. Treatment with lisinopril or lisW-S significantly reduced levels of AngII in kidneys (~4-fold; P<0.001). Ang-(2-8) [angiotensin-2-8)] was significantly reduced by lisinopril, but not by lisW-S. Plasma bradykinin levels were significantly increased only in the lisinopril group. These data suggest that C-domain-selective ACEIs reduce BP and AngII levels similarly to classical ACEIs. C-domain-selective ACEIs have the potential to avoid undesirable effects on the bradykinin system common to classic ACEIs and may represent a novel approach to the treatment of hypertension.

Green chemistry approaches as sustainable alternatives to conventional strategies in the pharmaceutical industry

Green chemistry is a rapidly developing field providing an avenue for the sustainable development of future science and technology. It offers enhanced chemical process economics, concomitant with a reduced environmental burden. It can be applied to design environmentally benign synthetic protocols to deliver life-saving medicines, while minimizing environmental impact. It is expected that chemists and chemical engineers should produce greener and more sustainable chemical processes for drug design and it is likely that this trend will continue to grow over the next few decades. This review summarizes environmentally benign protocols for the synthesis of some FDA (Food and Drug Administration) approved drugs which are in high volume demand coupled with their requirements of high chemical and optical purity utilizing the principles of green chemistry.

Pharmacokinetic evaluation of lisinopril-tryptophan, a novel C-domain ACE inhibitor

Angiotensin-converting enzyme (ACE, EC 3.4.15.1) is a metallopeptidase comprised of two homologous catalytic domains (N- and C-domains). The C-domain cleaves the vasoactive angiotensin II precursor, angiotensin I, more efficiently than the N-domain. Thus, C-domain-selective ACE inhibitors have been designed to investigate the pharmacological effects of blocking the C-terminal catalytic site of the enzyme and improve the side effect profile of current ACE inhibitors. Lisinopril-tryptophan (LisW-S), an analogue of the ACE inhibitor lisinopril, is highly selective for the C-domain. In this study, we have analysed the ex vivo domain selectivity and pharmacokinetic profile of LisW-S. The IC50 value of LisW-S was 38.5 nM in rat plasma using the fluorogenic substrate Abz-FRKP(Dnp)P-OH. For the pharmacokinetics analysis of LisW-S, a sensitive and selective LC-MS/MS method was developed and validated to determine the concentration of LisW-S in rat plasma. LisW-S was administered to Wistar rats at a dose of 1 mg/kg bodyweight intravenously, 5 mg/kg bodyweight orally. The Cmax obtained following oral administration of the drug was 0.082 μM and LisW-S had an apparent terminal elimination half-life of around 3.1 h. The pharmacokinetic data indicate that the oral bioavailability of LisW-S was approximately 5.4%. These data provide a basis for better understanding the absorption mechanism of LisW-S and evaluating its clinical application.

Synthesis and medicinal chemistry of selected antitubercular natural products and natural product derivatives

Despite advances in molecular methods for the diagnosis of tuberculosis (TB) and its resistant forms, it remains more prevalent in the world today than at any other time in human history. Of equal concern is the slow moving antitubercular drug development pipeline which calls for research efforts to be intensified and directed towards the discovery of new molecular scaffolds and/or the remodelling of some old TB drug families. In support of the latter, this review highlights synthetic methodologies and structure activity relationships (SARs) elaborated for natural products and/or natural product derivatives with promising antitubercular activity. It further attests to the enormous potential of natural products in the antitubercular drug discovery process.